Parkinson disease Primer Nature.pdf

PRIMER Parkinson disease Werner Poewe1, Klaus Seppi1, Caroline M. Tanner2,3, Glenda M. Halliday4,5,...

PRIMER Parkinson disease Werner Poewe1, Klaus Seppi1, Caroline M. Tanner2,3, Glenda M. Halliday4,5, Patrik Brundin6, Jens Volkmann7, Anette-Eleonore Schrag8 and Anthony E. Lang9 Abstract | Parkinson disease is the second-most common neurodegenerative disorder that affects 2–3% of the population ≥65 years of age. Neuronal loss in the substantia nigra, which causes striatal dopamine deficiency, and intracellular inclusions containing aggregates of α‑synuclein are the neuropathological hallmarks of Parkinson disease. Multiple other cell types throughout the central and peripheral autonomic nervous system are also involved, probably from early disease onwards. Although clinical diagnosis relies on the presence of bradykinesia and other cardinal motor features, Parkinson disease is associated with many non-motor symptoms that add to overall disability. The underlying molecular pathogenesis involves multiple pathways and mechanisms: α‑synuclein proteostasis, mitochondrial function, oxidative stress, calcium homeostasis, axonal transport and neuroinflammation. Recent research into diagnostic biomarkers has taken advantage of neuroimaging in which several modalities, including PET, single-photon emission CT (SPECT) and novel MRI techniques, have been shown to aid early and differential diagnosis. Treatment of Parkinson disease is anchored on pharmacological substitution of striatal dopamine, in addition to non-dopaminergic approaches to address both motor and non-motor symptoms and deep brain stimulation for those developing intractable l‑DOPA-related motor complications. Experimental therapies have tried to restore striatal dopamine by gene-based and cell-based approaches, and most recently, aggregation and cellular transport of α‑synuclein have become therapeutic targets. One of the greatest current challenges is to identify markers for prodromal disease stages, which would allow novel disease-modifying therapies to be started earlier. Two hundred years after James Parkinson’s seminal essay and quality of life (QOL) up to decades after disease on ‘the shaking palsy’, most of his original clinical obser- onset. However, none of these treatments is curative vations have stood the test of time. Beyond the perception and Parkinson disease remains a progressive disorder of Parkinson disease as a disorder of movement, it has that eventually causes severe disability — not least by since become apparent that a multitude of non-­motor the increasing severity of treatment-resistant motor features, such as cognitive impairment, autonomic dys- problems and non-motor symptoms. Thus, modifying function, disorders of sleep, depression and hyposmia disease progression and further delaying disability are (impaired smell), are part of the disease and add consid- the key unmet needs to be addressed by current and erably to overall burden. Tremendous progress has been future research efforts. Of great future potential is the made in understanding the neuro­pathology of Parkinson development of methods to identify individuals at risk disease and its progression throughout the nervous sys- and early manifestations that antedate the onset of the tem, as well as the molecular and neuro­physiological defining motor symptoms. mechanisms and perturbations underlying the disease In this Primer, we describe the epidemiology of and its symptoms. Above all, highly efficacious therapies Parkinson disease, and review our current under- Correspondence to W.P. have become available, which are focused on pharmaco- standing of the underlying pathology and molecular Department of Neurology, logical dopamine substitution (l‑DOPA treatment), but pathogenesis as well as the perturbations of basal gan- Medical University Innsbruck, with important refinements and ground-breaking expan- glia and cortical connectivity that underlie the cardinal Anichstrasse 35, sions, such as the introduction of deep brain stimulation motor features of this illness. We also summarize recent A-6020 Innsbruck, Austria. werner.poewe@i‑med.ac.at (DBS). These treatment advances have undoubtedly advances in clinical diagnostics, biomarker research made Parkinson disease the first and still unparalleled and screening, and provide an overview of the natural Article number: 17013 doi:10.1038/nrdp.2017.13 example of a neuro­degenerative disease that can be effec- history of Parkinson disease and the current, as well as Published online 23 Mar 2017 tively managed, leading to sustained symptom control future, therapies. NATURE REVIEWS | DISEASE PRIMERS VOLUME 3 | ARTICLE NUMBER 17013 | 1 © 2 0 1 7 M a c m i l l a n P u b l i s h e r s L i m i t e d , p a r t o f S p r i n g e r N a t u r e. A l l r i g h t s r e s e r v e d. PRIMER Author addresses populations, and societal rather than biological causes might underlie these findings3. Geography and race 1 Department of Neurology, Medical University Innsbruck, are often related, and it might be difficult to determine Anichstrasse 35, A-6020 Innsbruck, Austria. the relative contribution of each to the risk of develop- 2 Parkinson’s Disease Research Education and Clinical ing Parkinson disease. In Israel, the prevalence is high, Center, San Francisco Veteran’s Affairs Medical Center, possibly reflecting the higher prevalence of the incom- San Francisco, California, USA. 3 Department of Neurology, University of California pletely penetrant genes associated with Parkinson disease — San Francisco, San Francisco, California, USA. (that is, LRRK2 (which encodes leucine-rich repeat serine/­ 4 Brain and Mind Centre, Sydney Medical School, University threonine-­protein kinase 2) and GBA (which encodes of Sydney, Sydney, New South Wales, Australia. gluco­cerebrosidase)) in Ashkenazi Jews13. The prevalence 5 Faculty of Medicine, University of New South Wales of Parkinson disease is also high in Inuit, Alaska Native & Neuroscience Research Australia, Sydney, New South and Native American populations14. Lifestyle, includ- Wales, Australia. ing diet­ary exposure to persistent organic pollutants, or 6 Van Andel Research Institute, Center for shared genetic factors could explain this pattern. The Neurodegenerative Science, Grand Rapids, Michigan, USA. incidence is greater in men of Japanese and Okinawan 7 Department of Neurology, University Hospital of descent living in Hawaii than in men living in Japan, sup- Würzburg, Würzburg, Germany. 8 Department of Clinical Neuroscience, UCL Institute of porting that environ­mental factors have a role15. Gene– Neurology, London, UK. environment interactions defin­itely modify the risk for 9 Division of Neurology, Department of Medicine, sporadic Parkinson disease. For example, the incidence University of Toronto, Toronto, Ontario, Canada. of Parkinson disease is signifi­cantly greater in individuals exposed to certain environ­mental factors, such as pesti- Epidemiology cides and traumatic brain injury, and lower in smokers or Worldwide incidence estimates of Parkinson disease caffeine users16. range from 5 to >35 new cases per 100,000 individuals yearly 1, which probably reflects differences in the demo- Mechanisms/pathophysiology graphics of the populations studied or in study methods. Neuropathology In a population-based study in Minnesota (USA) with Characteristic features of Parkinson disease include pathological validation of clinical diagnoses, the inci- neuro­nal loss in specific areas of the substantia nigra and dence of Parkinson disease was 21 cases per 100,000 widespread intracellular protein (α‑synuclein) accumula- person-­years2. Parkinson disease is rare before 50 years of tion. Although neither the loss of pigmented dopaminer- age1, but the incidence increases 5–10‑fold from the sixth gic neurons in the substantia nigra17,18 nor the deposition to the ninth decade of life1–3. The global prevalence, con- of α‑synuclein in neurons is specific for Parkinson dis- servatively estimated at 0.3% overall, likewise increases ease, these two major neuropathologies are specific for a sharply with age to >3% in those >80 years of age4 (FIG. 1). definitive diagnosis of idiopathic Parkinson disease when Mortality is not increased in the first decade after dis- applied together (FIG. 2). ease onset, but increases thereafter, eventually doubling Gross macroscopic atrophy of the brain is not a fea- compared with the general population5. Improvement in ture of Parkinson disease, rather neuronal degeneration health care has led to longer survival, which is associated occurs in only certain types of neurons within particular with increasing prevalence of Parkinson disease over brain regions. In early-stage disease, loss of dopaminergic time in one 20‑year study 6. The number of people with neurons is restricted to the ventrolateral substantia nigra Parkinson disease is expected to double between 2005 with relative sparing of other midbrain dopaminergic and 2030 (REF. 7). Years lived with disability and disability- neurons19,20 (FIG. 2a–d), but becomes more widespread adjusted life years due to Parkinson disease increased by end-stage disease. The dramatic loss of these dopa- between 1990 and 2010, and a progressive increase in minergic neurons even early in the disease suggests that the personal, societal and economic burden associated the degeneration in this region starts before the onset of with the disease is expected in the future as the world motor symptoms, which is supported by several recent ­population ages7–10. clinicopathological studies21,22. Parkinson disease is twice as common in men than in The other required neuropathology is the abnormal women in most populations3,11 (FIG. 1), although in a few deposition of α‑synuclein in the cytoplasm of certain populations, including one study from Japan, no differ- neurons in several different brain regions23. Lewy bodies, ence or even a female excess was observed12. A protective which are largely made up of aggregated ­α‑synuclein, were effect of female sex hormones, a sex-associated genetic the first to be described over a century ago. Following the mechanism or sex-specific differences in exposure to development of refined histopathological methods, environmental risk factors might explain this male pre- a broader range of α‑synuclein aggregates have been ponderance, although disparities in health care could described (FIG. 2e–g). The Lewy pathology initially occurs also contribute. in cholinergic and monoaminergic brainstem neurons The incidence seems to vary within subgroups defined and in neurons in the olfactory system, but is also found by race, ethnicity, genotype or environment. Parkinson in limbic and neocortical brain regions with disease pro- disease might be less common in African Americans and gression (FIG. 2h). In patients with Alzheimer pathology, Asians in the United States, but systematic race-specific there is a different pattern of α‑synuclein pathology that incidence has not been investigated in other multiracial concentrates mainly in limbic brain regions22. 2 | ARTICLE NUMBER 17013 | VOLUME 3 www.nature.com/nrdp © 2 0 1 7 M a c m i l l a n P u b l i s h e r s L i m i t e d , p a r t o f S p r i n g e r N a t u r e. A l l r i g h t s r e s e r v e d.  PRIMER Although heritable forms of Parkinson disease only monomers initially form oligomers, then progressively represent 5–10% of all cases (TABLE 1), they have provided combine to form small protofibrils and eventually large, crucial clues to the mechanisms underlying the neuro- insoluble α‑synuclein fibrils (that is, the aggregates that pathology of Parkinson disease. Some of the proteins make up Lewy pathology)29,30. The underlying triggers encoded by genes associated with Parkinson disease of accumulation and aggregation of α‑synuclein can are involved in a set of molecular pathways that, when be manifold, for example, a relative overproduction perturbed, can trigger a neuropathology that resem- of the protein, the presence of mutations that increase bles, or is indistinguishable from, sporadic Parkinson the likeli­hood for its misfolding and oligomerization or disease. In addition, large genome-wide association impairments in the molecular pathways that are charged studies (GWAS) confirm that some of these genes are with degrading native or misfolded α‑synuclein. also affected in sporadic Parkinson disease24. Examples A progressive, age-related decline in proteolytic of these pathways are: α‑synuclein proteostasis, mito­ defence mechanisms in the ageing brain might play an chondrial function, oxidative stress, calcium h ­ omeostasis, important part in the accumulation of α‑synuclein31,32 axonal transport and neuroinflammation (FIG. 3). (FIG. 3). α‑Synuclein proteostasis α‑Synuclein degradation. Intracellular homeo­stasis Intraneuronal protein aggregates that are largely made up of α‑synuclein is maintained by the actions of the of α‑synuclein are found in all patients with Parkinson ubiquitin–­proteasome system and the lysosomal auto- disease. The existence of point mutations and multi­ phagy system (LAS). The relative importance of the plications of SNCA, the gene encoding ­α‑synuclein, ubiquitin–­proteasome system and LAS for intracellu- that cause heritable forms of Parkinson disease strongly lar α‑synuclein proteolysis in neurons is debated and support the notion that α‑synuclein is a key player LAS seems to be more important than the ubiquitin–­ in Parkinson disease (TABLE 1). Similarly, GWAS have proteasome system to clear oligomeric assemblies32. revealed a single-nucleotide polymorphism associated With respect to LAS, both chaperone-mediated auto- with the SNCA locus that alters the risk for sporadic phagy and macroautophagy are suggested to mediate Parkinson disease and is associated with increased α‑synuclein degradation32,33. Chaperone-mediated auto- expression levels of α-synuclein24,25. A study in human phagy involves specific chaperones that target certain neurons derived from induced pluripotent stem cells and proteins to lysosomes, whereas macroautophagy entails post-mortem frontal cortex samples from patients with the formation of autophagosomes that are directed Parkinson disease supports the idea that a risk variant to perinuclear lysosomes. Inhibition of either system associated with Parkinson disease in a non-coding dis- leads to increased levels of α‑synuclein, and evidence tal enhancer element of SNCA is coupled to increased for some compensatory crosstalk between the systems α‑synuclein expression26. exists34. Additional proteases, which are not part of the The normal neuronal function of the 140 amino ubiquitin–proteasome system and LAS, can also cleave acid α‑synuclein protein is not fully understood, but α‑synuclein in the extracellular space32. it occurs in the cytosol, possibly also in mitochondria Several lines of evidence suggest that impairment and the nucleus, and probably has a role in synaptic of these degradation systems could contribute to vesicle dynamics, mitochondrial function, intracellu- ­α‑synuclein accumulation. Increasing age — the great- lar trafficking and might be a potential chaperone25,27,28. est risk factor for Parkinson disease — is associated α‑Synuclein acquires neurotoxic properties during with reduced LAS and ubiquitin–proteasome system a pathogenetic process in which soluble α‑synuclein functions31, which is consistent with observations of a 2,500 b 300 Incidence rates (per 100,000 person-years) Prevalence (per 100,000 individuals) Men 250 2,000 Women 200 1,500 150 1,000 100 500 50 0 0 0 40–49 50–59 60–69 70–79 >80 0 40–49 50–59 60–69 70–79 >80 Age (years) Age (years) Figure 1 | Incidence and prevalence of Parkinson disease. a | Prevalence of Parkinson disease NatureinReviews men and womenPrimers | Disease per 100,000 individuals. b | Incidence rate of Parkinson disease per 100,000 person-years. Data are derived from two recent meta-analyses, which used crude rates without adjustments for demographic differences or methodological differences between studies4,235. NATURE REVIEWS | DISEASE PRIMERS VOLUME 3 | ARTICLE NUMBER 17013 | 3 © 2 0 1 7 M a c m i l l a n P u b l i s h e r s L i m i t e d , p a r t o f S p r i n g e r N a t u r e. A l l r i g h t s r e s e r v e d. PRIMER increased levels of α‑synuclein in nigral dopaminergic are decreased39 and autophagosomes accumulate40. neurons during normal ageing 35. Pharmacological stim- Additional observations support the idea that altered ulation of macroautophagy reduces the levels of intra- proteostasis profoundly influences neuronal accumu­ cellular α‑synuclein in experimental models36,37. In the lation of α‑synuclein. For example, α‑synuclein oli- substantia nigra of patients and experimental models of gomers inhibit the ubiquitin–­proteasome system41, Parkinson disease, lysosomal enzyme levels are reduced, accumulating α‑synuclein can inhibit macroauto- particularly in neurons containing ­α‑synuclein inclu- phagy 42,43 and different forms of α‑synuclein (wild sions38, markers of chaperone-mediated autophagy type, mutant or post-translationally modified) can reduce chaperone-­mediated autophagy function34,44. Collectively, these observations suggest a vicious cycle a Control PD b involving the accumu­lation of α‑synuclein due to dis- rupted proteostasis, which in turn leads to defective α‑synuclein degradation. Several mutations associated with genetic forms of c Parkinson disease are associated with reduced LAS func- tion. The G2019S mutation in the gene encoding LRRK2 RN RN is associated with impaired LAS and increased aggrega- SN tion of α‑synuclein in dopaminergic neurons that are SN 3N d exposed to α‑synuclein fibrils45. Heterozygous mutations in the gene encoding the lysosomal enzyme GBA, the CP most common genetic risk factor for Parkinson dis- 500 μm 200 μm ease46, are coupled to reduced LAS function47. GWAS e f g have revealed two polymorphisms in the GBA locus associ­ated with altered risk of developing Parkinson disease24, and normal ageing is reported to result in a progressive decline in GBA activity 48. Recent evidence from clinical cohort studies also suggests an increased risk for dementia in individuals with Parkinson disease who carry GBA mutations that, in the homo­zygotic 10 μm 50 μm 20 μm state, are associated with the neuronopathic type of Gaucher disease49,50. Reduced GBA activity coincides h with increased levels of α‑synuclein both in cell cultures and animal models51,52. Mutations in the gene encoding vacuolar protein sorting-associated protein 35 (VPS35), which cause auto­somal dominant Parkinson disease53,54, also seem to affect α‑synuclein handling. VPS35 is part of the retromer complex, which has a key role in sorting lipids and proteins that are newly synthesized or have undergone endocytosis and directs them to Braak stage I and stage II Braak stage III and stage IV Braak stage V and stage VI either the lysosome, the cell surface or the Golgi appar­ Cortical Lewy body atus55. Notably, Vps35‑deficient mice exhibit increased Severity of pathology Lewy body in the substantia nigra ­levels of ­α‑synuclein in nigral dopaminergic neurons56, whereas overexpression of Vps35 reduces α‑synuclein Figure 2 | The main diagnostic neuropathologies for Parkinson disease. Nature Reviews a | Parkinson | Disease Primers accumulation in transgenic mice who also overexpress disease (PD) is defined by depigmentation of the substantia nigra (SN) (right panel) α‑synuclein and in cultured neurons that are exposed compared with control (left panel). Macroscopical (inset) and transverse sections of the to α‑synuclein fibrils57. Both VPS35 deficiency and midbrain upon immunohistochemical staining for tyrosine hydroxylase, the rate limiting enzyme for the synthesis of dopamine, are shown. Selective loss of the ventrolateral parts the D620N mutation in VPS35 that causes autosomal of the SN with sparing of the more medial and dorsal regions is evident in the histological dominant Parkinson disease are coupled to reduced section. b–d | Haematoxylin and eosin staining of the ventrolateral region of the SN cellular levels of lysosome-associated membrane glyco- showing a normal distribution of pigmented neurons in a healthy control (part b) and protein 2 (LAMP2)56, suggesting once again that LAS diagnostically significant moderate (part c) or severe (part d) pigmented cell loss in PD. perturbation is key to disease pathogenesis. Finally, e–g | Immunohistochemical staining of α‑synuclein shows the round, intracytoplasmic mutations in ATP13A2 (also known as PARK9), which Lewy bodies (arrow in part e), more diffuse, granular deposits of α‑synuclein (part e and encodes a type 5 P‑type ATPase that is present in lyso­ part f), deposits in neuronal cell processes (part f), extracellular dot-like α‑synuclein somes and autophagosomes58, are associ­ated with a structures (part f) and α‑synuclein spheroids in axons (part g). h | The theorized rare juvenile-onset neurological condition (Kufor– progression of α‑synuclein aggregation in PD without Alzheimer pathology. α‑Synuclein Rakeb syndrome) that includes parkin­sonian features inclusions occur in cholinergic and monoaminergic lower brainstem neurons in asymptomatic cases (Braak stage I and stage II), infiltrate similar neurons in the midbrain and responds to dopaminergic therapy 58. Dysfunction and basal forebrain in those with the motor symptoms of PD (Braak stage III and stage IV), of LAS and vesicular trafficking probably contribute and then are found later in limbic and neocortical brain regions with disease progression to neuro­degeneration in people with mutations in (Braak stage V and stage VI)236. 3N, 3rd nerve fibres; CP, cerebral peduncle; RN, red nucleus. ATP13A2 (REF. 59). Notably, GWAS have revealed that Part h adapted with permission from REF. 236, Wiley. certain ATP13A2 variants are associated with increased 4 | ARTICLE NUMBER 17013 | VOLUME 3 www.nature.com/nrdp © 2 0 1 7 M a c m i l l a n P u b l i s h e r s L i m i t e d , p a r t o f S p r i n g e r N a t u r e. A l l r i g h t s r e s e r v e d.  PRIMER Table 1 | Classification of hereditary parkinsonism* Locus New Gene Gene OMIM (phenotype Clinical clues symbol designation‡ locus MIM number; gene/ locus MIM number) Autosomal dominant Parkinson disease PARK1 or PARK-SNCA 4q22.1 SNCA 168601; 163890 Missense mutations (PARK1) cause classic Parkinson disease PARK4 (PARK1) phenotype. Duplication or triplication of this gene (PARK4) 605543; 163890 causes early-onset Parkinson disease with prominent dementia (PARK4) PARK8 PARK‑LRRK2 12q12 LRRK2 607060; 609007 Classic Parkinson disease phenotype. Variations in LRRK2 include risk-conferring variants and disease-causing mutations PARK17 PARK‑VPS35 16q11.2 VPS35 614203; 601501 Classic Parkinson disease phenotype Early-onset Parkinson disease (autosomal recessive inheritance) PARK2 PARK-Parkin 6q26 PARK2 encoding 600116; 602544 Often presents with lower limb dystonia parkin PARK6 PARK‑PINK1 1p36.12 PINK1 605909; 608309 Psychiatric features are common PARK7 PARK‑DJ1 1p36.23 PARK7 encoding 606324; 602533 Early-onset Parkinson disease protein deglycase DJ1 PARK19B PARK‑DNAJC6 1p31.3 DNAJC6 615528; 608375 Onset of parkinsonism between the third and fifth decades of life Complex genetic forms (autosomal recessive inheritance)§ PARK9 PARK‑ATP13A2 1p36.13 ATP13A2 606693; 610513 Early-onset parkinsonism with a complex phenotype (for example, dystonia, supranuclear gaze palsy, pyramidal signs and cognitive dysfunction); also known as Kufor–Rakeb syndrome PARK14 PARK‑PLA2G6 22q13.1 PLA2G6 256600; 603604 PLAN (or NBIA2) is characterized by a complex clinical phenotype, which does not include parkinsonism in the majority of cases PARK15 PARK‑FBXO7 22q12.3 FBXO7 260300; 605648 Early-onset parkinsonism with pyramidal signs and a variable complex phenotype (for example, supranuclear gaze palsy, early postural instability, chorea and dystonia) PARK19A PARK‑DNAJC6 1p31.3 DNAJC6 615528; 608375 Juvenile-onset parkinsonism that is occasionally associated with mental retardation and seizures PARK20 PARK‑SYNJ1 21q22.11 SYNJ1 615530; 604297 Patients may have seizures, cognitive decline, abnormal eye movements and dystonia PARK23 Not yet 15q22.2 VPS13C 616840; 608879 Young-adult-onset parkinsonism associated with progressive assigned cognitive impairment that leads to dementia and dysautonomia The locus symbols are in accordance with the Online Mendelian Inheritance in Man (OMIM) catalogue (https://omim.org). Seven loci, which have been assigned a PARK designation, have a yet unconfirmed relationship to disease (that is, PARK3, unknown gene on 2p13; PARK5, UCHL1 on 4p13; PARK11, GIGYF25 on 2q37.1; PARK13, HTRA2 on 2p13.1; PARK18, ELF4G1 on 3q27.1; PARK21, DNAJC13 on 3q22; and PARK22, CHCHD2 on 7p11.2) and three are classified as risk loci (PARK10 on 1p32; PARK12 on Xq21–q25; and PARK16 on 1q32). Mutations in TMEM230 on 20p12 have also very recently been described to cause monogenic Parkinson disease, but causal relationship to disease is still uncertain134,240. MDS, International Parkinson and Movement Disorder Society; NBIA2, neurodegeneration with brain iron accumulation 2A; PLAN, PLA2G6‑associated neurodegeneration. *See REFS 133,241. ‡On the basis of the recommendations of the MDS Task Force on the nomenclature of genetic movement disorders, which will be regularly updated: MDSGene; available at http://www.mdsgene.org133,241. §Complex genetic forms that have parkinsonism as a key clinical feature but also present with atypical, multisystem features or other movement disorders. penetrance of LRRK2 mutations and increased risk of space through exosomes and that endo­cytosis is a key Parkinson disease in GBA mutation carriers, which sup- mechanism of uptake of extracellular α‑synuclein63,64. ports the idea that the proteins encoded by these genes Thus, initial α‑synuclein misfolding in a small ­number of act in shared molecular pathways60. cells could progressively lead to the spread of α ­ ‑synuclein aggregates to multiple brain regions over years or d ­ ecades Prion-like propagation of α‑synuclein. An addi- following the initial insult. This is consistent with the idea tional mechanism for the development of α‑synuclein that α ­ ‑synuclein pathology gradually engages more brain aggregates has recently been proposed. The prion-like regions as the disease progresses, as suggested by Braak hypothesis for α‑synuclein posits that once α ­ ‑synuclein et al.23 (FIG. 2h). In addition, this model supports the idea aggregates have formed in a neuron, they can be trans- that the first sites of α‑synuclein aggregation might be ported intra-axonally to other brain regions, be released in the gut enteric nerves and the olfactory bulb where into the extracellular space, be taken up by neighbour­ing they underlie the signs and symptoms associated with neurons and seed aggregation of endogen­ous α ­ ‑­synuclein prodromal Parkinson disease (for example, anosmia once inside their new cellular host 61,62. Cell culture stud- and constipation)65,66, before they spread, eventually ies have demonstrated that LAS impairment leads to leading to motor dysfunction once the substantia nigra increased secretion of α‑synuclein into the extracellular becomes involved67. NATURE REVIEWS | DISEASE PRIMERS VOLUME 3 | ARTICLE NUMBER 17013 | 5 © 2 0 1 7 M a c m i l l a n P u b l i s h e r s L i m i t e d , p a r t o f S p r i n g e r N a t u r e. A l l r i g h t s r e s e r v e d. PRIMER Neuroinflammation Neuron Activated microglia Unfolded α-synuclein Reactive oxygen species Perturbed α-synuclein proteostasis Impaired mitochondrial biogenesis Toxic oligomers Mitochondrial Oxidative Misfolding Macroautophagy Chaperone-mediated dysfunction stress of protein autophagy Calcium Calcium influx channel Autophagosome β-Pleated sheet Impaired Lysosomal autophagy calcium system homeostasis Lysosome-dependent degradation Nucleus Caspase Ubiquitin–proteasome activation system Lewy body Trans-synaptic transmission to Cell unaffected neurons death Figure 3 | Molecular mechanisms involved in Parkinson disease. Schematic diagram depicting interactions Nature Reviews between | Disease Primers major molecular pathways that are implicated in the pathogenesis of Parkinson disease. Mitochondrial dysfunction that impair mitochondrial function replicates features Several lines of evidence have implicated mitochondrial of Parkinson disease neuropathology 68,69. When mito- dysfunction as a key element in the pathogenesis of chondrial transcription factor A, which is essential Parkinson disease (reviewed in detail in REFS 68,69; FIG. 3). for mitochondrial DNA expression, is selectively An emerging picture is one of a vicious cycle in which depleted in dopaminergic neurons of mice — so-called α‑synuclein aggregation and mitochondrial dysfunction MitoPark mice — mitochondria in dopaminergic neu- exacerbate each other, which could explain why these rons in the substantia nigra develop a defective elec- cellular changes are observed together in degenerating tron transport chain, leading to neuronal degeneration neurons in Parkinson disease. in adulthood73. Adult mice that lack one allele of En1 Activity of mitochondrial complex I, a compound — encoding for engrailed 1, which enhances nuclear of the electron transport chain, is reduced in several translation of the mitochondrial complex proteins ­t issues isolated from patients with Parkinson dis- NADH-ubiquinone oxidoreductase 75 kDa subunit ease68,69. Peroxisome proliferator-activated receptor-γ (NDUFS1) and NDUFS3 — replicate several important (PPARγ) co-activator 1α (PGC1α), a mitochondrial features of Parkinson disease neuropathology, such as master transcriptional regulator, target genes are gen- perturbations of autophagy, neuroinflammation and erally under­expressed in Parkinson disease70. It has been progressive nigral dopaminergic neuron death follow­ing proposed that low levels of α‑synuclein are normally retrograde axonal degeneration74. Importantly, axonal present in mitochondria, but that accumulation of the degeneration, potentially owing to the energy deficiency, protein inside mitochondria leads to mitochondrial might be an upstream and early neuro­degenerative complex I deficits and oxidative stress71. Activation of event in Parkinson disease. Human brain imaging PGC1α results in reduced α‑synuclein oligomerization studies have demonstrated changes in the s­ triatum and less toxicity in vitro, whereas induced PGC1α defi- in ­people with Parkinson disease even several years ciency by genetic knockdown increases vulnerability before they are diagnosed75,76, and recent post-mortem to ­α‑synuclein oligo­mers72. Conversely, exposure to studies suggest that nigrostriatal axon terminals are ­α‑synuclein oligo­mers reduces the levels of cellular dysfunctional or have degenerated several years before PGC1α72. In animal models, injection of several toxins the neuronal cell bodies in the substantia nigra die77. 6 | ARTICLE NUMBER 17013 | VOLUME 3 www.nature.com/nrdp © 2 0 1 7 M a c m i l l a n P u b l i s h e r s L i m i t e d , p a r t o f S p r i n g e r N a t u r e. A l l r i g h t s r e s e r v e d.  PRIMER An alternative explanation for the axonal degener­ with Parkinson disease and cultured dopaminergic neu- ation is that ­α‑synuclein aggregates eventually become rons (when exposed to activated microglia or l‑DOPA) obstacles to normal axonal transport 78. have been reported to be particularly inclined to express Recent advances in the understanding of molecular MHC class I proteins, which exposes them to cytotoxic pathways governed by proteins encoded by genes associ­ T cell-mediated death if they present antigens95. ated with Parkinson disease have provided additional GWAS indicate that genes associated with the risk of support to the notion that mitochondrial failure is a key developing Parkinson disease often encode proteins that event in disease process. For example, LRRK2 mutations are expressed in immune cells and that are involved in are not only associated with changes in autophagy but immune regulation, such as LRRK2 (which is involved also with mitochondrial impairments69. Moreover, pro- in autophagy by immune cells)24,96,97. Close links between teins encoded by PARK2 and PINK1, which are auto- certain genes, protein aggregates and neuroinflammation somal recessive Parkinson disease genes, cooperate in exist. Evidence from patients and experimental mod- the clearance of damaged mitochondria through mito- els suggests that α‑synuclein aggregation induces both phagy 79. Impaired degradation of MIRO (a protein in innate and adaptive immunity in Parkinson disease93,94 the outer mitochondrial membrane that connects the and neuroinflammation can also promote α‑synuclein organelle to microtubule motors) seems to have a role misfolding 98, suggesting that the two processes partici­ in defective clearance of damaged mitochondria. In neu- pate in a self-aggravating cycle. During prodromal rons derived from induced pluripotent stem cells from Parkinson disease, tissue inflammation in the olfactory patients with inherited or sporadic Parkinson disease, system or gut has been suggested to trigger a sufficient degradation of MIRO is reduced, and as a consequence, level of α‑synuclein misfolding that some α‑synuclein mitophagy is inefficient, which ultimately could lead to aggregates eventually escape the normal degradation energy failure80. mechanisms99. Indeed, recent evidence from experiments in Snca-overexpressing mice suggests a role of gut micro- Oxidative stress biota in promoting microglial activation and α‑synuclein Evidence that oxidative stress, as a consequence of mito- pathology, as well as motor deficits100. chondrial dysfunction, is increased in the brain tissue of However, it would be misleading to suggest that acti- patients with Parkinson disease is compelling 81 (FIG. 3), vated immune cells only contribute to the initiation or but it is debatable whether it occurs early or late during deterioration of Parkinson disease pathology in the brain. the demise of neurons. Mutations in DJ1 (also known as Microglia can phagocytose and degrade extra­cellular PARK7), encoding a putative antioxidant, which cause α‑synuclein aggregates, and immuno­therapies that t­ arget early-onset autosomal recessive Parkinson disease82, are α‑synuclein, which are currently being developed for associated with increased cellular oxidative stress83,84. clinical trials, rely on the clearance of antibody-bound Knocking out Dj1 in mice results in increased protein α‑synuclein by activated immune cells101. oxidation in stressed nigral dopaminergic neurons. Nigral dopaminergic neurons have been suggested Motor circuit pathophysiology to be particularly vulnerable to metabolic and oxid­ The basal ganglia are part of several parallel, but anatom­ ative stress for several reasons. First, they possess ically segregated thalamo–cortico–basal ganglia circuits, particu­larly long (up to 4.5 metres), unmyelinated which have important functions in the control of actions axons, with large numbers of synapses (estimated at and goal-directed behaviour. These circuits are anatom- 1–2.4 ­million per nigral dopaminergic neuron), which ically characterized by a strong convergence of cortical require great energy to be sustained85,86. Second, they input onto relatively few subcortical output neurons (unlike the dopaminergic neurons in the neighbouring and back to the cortex, suggesting a ‘filter-like’ func- ventral tegmental area, which are relatively resilient in tion. Four circuits with a functionally similar, yet topo­ Parkinson disease) exhibit autonomous pacemaking graphically distinct, organization have been identified activity involving cytosolic calcium oscillations and to subserve limbic, prefrontal-associative, oculo­motor calcium extrusion at the expense of energy 87,88. Third, and motor functions by linking the corresponding fron- increased levels of cytosolic dopamine and its metabo­ tal cortical areas and subregions of the thalamus and lites can cause toxic oxidative stress89,90. Last, mito- basal ganglia102,103. chondrial dysfunction and increased oxidative stress Parkinsonism results from a decreased dopamin- can lead to the depletion of lysosomes91 and functional ergic transmission in the motor region of the striatum impairment of LAS, further demonstrating that several with opposing effects on the direct and indirect path- putative pathogenetic ­pathways in Parkinson disease are ways, which results in increased γ‑aminobutyric acid intimately linked. (GABA)-ergic inhibition of thalamocortical projections (FIG. 4). This firing rate model provided a rationale for the Neuroinflammation renaissance of stereotactic surgery for Parkinson disease A large number of post-mortem, brain imaging and fluid in the early 1990s, as akinesia was no longer considered biomarker studies shows that neuroinflammation is a a loss‑of‑function symptom, but rather the physiolog- salient feature of Parkinson disease92 (FIG. 3). Although ical consequence of increased inhibitory output activ- maybe not the initial trigger, neuroinflammation is ity of the basal ganglia. Indeed, lesioning of the globus probably an essential contributor to pathogenesis93,94. pallidus internus or the subthalamic nucleus proved to Catecholaminergic neurons in the brain tissue of patients be effective in alleviating bradykinesia in animals and NATURE REVIEWS | DISEASE PRIMERS VOLUME 3 | ARTICLE NUMBER 17013 | 7 © 2 0 1 7 M a c m i l l a n P u b l i s h e r s L i m i t e d , p a r t o f S p r i n g e r N a t u r e. A l l r i g h t s r e s e r v e d. PRIMER humans104,105. Meanwhile, the model has been amended However, changes in firing rate are not capable of by additional connections, such as the ‘hyperdirect fully explaining the pathophysiology of hyperkinetic pathway’, a monosynaptic link between motor cortical or hypokinetic movement disorders. Growing evidence areas and the subthalamic nucleus, which changed the suggests that movement disorders are characterized perception of the subthalamic nucleus from a passive by more-complex changes in information processing, relay nucleus to a second input structure of the basal such as abnormal neural synchronization and cortico–­ ganglia106. The hyperdirect pathway might have a role in subcortical coupling in specific frequency bands as preventing premature responses by reinforcing indirect indexed by electroencephalogram power density pathway activity and thereby the ‘breaking’ function of and spectral coherence. The parkinsonian off-state is the basal ganglia, thus allowing more time for the selec- character­ized by enhanced beta-band activity (~20 Hz) tion of the most appropriate response at the cortical in local field potential recordings from the basal ganglia, level107. Moreover, recent animal studies have suggested which is suppressed by dopaminergic medication or DBS that antidromic activation of the hyperdirect pathway in parallel with the clinical improvement of bradykinesia might drive the strong anti-akinetic effect of subthalamic and rigidity 110,111. By contrast, hyper­kinesia — such as nucleus DBS, which further underlines the functional l‑DOPA-­induced dyskinesia in Parkinson disease — significance of this second basal ganglia input 108,109. has been associated with increased theta-band activity in the same structures (4–12 Hz)112. High-frequency DBS ­suppresses either activity and might thus act like a ‘­filter’ (Associative) motor cortex for abnormally synchronized basal ganglia a­ ctivity, ­irrespective of the u ­ nderlying disorder. In addition, changes in cerebellar activity and the Striatum interaction between the basal ganglia and the cerebellum Direct Indirect might be important for the pathophysiology of tremor pathway pathway Hyperdirect in Parkinson disease113, and disorders of balance and pathway gait probably involve abnormal basal ganglia output via projections into the midbrain locomotor region (pedun- culopontine and cuneiform nuclei)114. A better under- Thalamus Substantia Globus standing of this expanded motor network may help to nigra pars pallidus compacta externus define alternative targets for DBS in Parkinson disease that target specific symptom profiles. Subthalamic nucleus Diagnosis, screening and prevention Clinical diagnosis and natural history Parkinson disease is clinically defined by the presence of Globus pallidus internus Substantia nigra pars reticulata bradykinesia and at least one additional cardinal motor feature (rigidity or rest tremor), as well as additional supporting and exclusionary criteria115–118 (BOX 1). Onset Mesencephalic motor regions of motor symptoms is usually uni­lateral and asym­ metry persists throughout the disease. The average age of onset is in the late fifties, with a broad range from Increased excitatory activity Increased inhibitory activity Reduced excitatory activity Reduced inhibitory activity 80 years of age. Young-onset Parkinson disease is commonly defined by an age of onset 10% of those individuals have a genetic basis, and the The motor circuit consists of corticostriatal projections from the primary motor cortex, proportion of genetically defined cases rises to >40% supplementary motor area, cingulate motor cortex and premotor cortex, terminating of those with disease onset before 30 years of age119,120. on dendrites of striatal medium spiny neurons. The hyperdirect pathway has direct In addition to the cardinal motor features, a majority glutamatergic connectivity from the motor cortex to the subthalamic nucleus. The globus pallidus internus and the substantia nigra pars reticulata are the two main of patients with Parkinson disease also have non-­motor output nuclei of the basal ganglia and project to the brainstem and ventrolateral symptoms121 (FIG. 5). Non-motor symptoms involve a thalamus. The striatal projections to these output nuclei are divided into ‘direct’ and multitude of functions, including disorders of sleep– ‘indirect’ pathways. The direct pathway is a monosynaptic connection between medium wake cycle regulation, cognitive impairment (includ- spiny neurons that express dopamine D1 receptors and GABAergic neurons in the globus ing frontal executive dysfunction, memory retrieval pallidus internus and the substantia nigra pars reticulata. The ‘indirect’ pathway deficits, dementia and hallucinosis), disorders of mood originates from medium spiny neurons that express D2 receptors, which project to the and affect, autonomic dysfunction (mainly orthostatic globus pallidus externus, and reaches the globus pallidus internus via the subthalamic hypotension, urogenital dysfunction, constipation and nucleus as a glutamatergic relay. Through these two pathways, the striatal dopaminergic hyperhidrosis), as well as sensory symptoms (most tone regulates the GABAergic output activity of the basal ganglia. As indicated, prominently hyposmia) and pain121. Some of these parkinsonism is associated with changes in these relays. Indeed, nigrostriatal dopamine deficiency has opposing effects on the direct and indirect pathways. Although can antedate the onset of classic motor symptoms by D1‑mediated direct pathway activity becomes reduced, D2‑mediated indirect pathway years or even decades. Non-motor symptoms become activity increases, resulting in the net effect of a strong increase in the firing rate of increasingly prevalent over the course of the illness and GABAergic basal ganglia output neurons, which over-inhibit downstream are a major determinant of QOL, progression of over- thalamocortical and brainstem areas. all disability and of nursing home placement. In one 8 | ARTICLE NUMBER 17013 | VOLUME 3 www.nature.com/nrdp © 2 0 1 7 M a c m i l l a n P u b l i s h e r s L i m i t e d , p a r t o f S p r i n g e r N a t u r e. A l l r i g h t s r e s e r v e d.  PRIMER meta-analysis of 11 studies assessing a UKPDSBB- Box 1 | MDS diagnostic criteria for Parkinson disease based clinical diagnosis against post-­mortem patho- Step 1: diagnosis of parkinsonism (core feature) logical examination as the gold standard 125. Such Presence of bradykinesia as a slowness of movement and a decrement in amplitude findings highlight the need for diagnostic tests and or speed (or progressive hesitations or halts) as movements are continued bio­markers to enhance diagnostic confidence in early In combination with at least one of: rigidity and/or r