Amyloid Filaments in Neurodegenerative Diseases

Tau Amyloid in Different Diseases

• Pick's disease is associated with narrow Pick filaments (6GX5) (Falcon et al, 2018)
• Alzheimer's disease (AD) is associated with paired helical filaments (5O3L) (Fitzpatrick et al, 2017)
• Corticobasal degeneration is associated with Type I filaments (6TJO) (Zhang et al, 2020)
• Chronic traumatic encephalopathy is associated with Type I filaments (6NWP) (Falcon et al, 2019)

Multiple Amyloid Conformers

• Multiple amyloid conformers can exist in the same individual, as seen in AD brain (Fitzpatrick et al, 2017)

Positron Emission Tomography (PET) Imaging

• PET imaging allows for the detection of amyloid within the brain following injection of a radiotracer (Chapleau et al, 2022)

Protein Misfolding and Conversion to Amyloid

• The process of protein misfolding and conversion to amyloid involves an intermediate state, small oligomers, and amyloid fibers growing by addition of monomers at their termini (Wang et al, 2022)

Aggregation and Protein Folding

• Aggregation is an off-pathway folding process (Adamcik, 2018)
• On-target and off-target protein folding landscapes exist (Adamcik, 2018)

Amyloid-Forming Proteins in Disease

• Amyloid-forming proteins are sometimes mutated in disease, but most frequently they are wild-type (Goate et al, 1991; Spillantini et al, 1998; Polymeropoulos et al, 1997; Rosen et al, 1993; Kabashi et al, 2008)

Amyloid in Non-Neurodegenerative Diseases

• Light chain amyloidosis (AL) is associated with immunoglobin light chain
• Heavy chain amyloidosis (HL) is associated with immunoglobin heavy chain
• AA amyloidosis is associated with serum amyloid A protein
• Various other diseases, including familial amyloid cardiomyopathy, dialysis-related amyloidosis, and hereditary non-neuropathic systemic amyloidosis, are associated with different amyloid-forming proteins

The HSP90 Chaperone Machinery

• The HSP90 chaperone machinery is involved in the proteostasis network and its decline in aging (Schopf et al, 2017; Hip et al, 2019)

Protein Aggregation in Killifish

• As killifish age, they undergo muscle deterioration, fertility decline, cognitive impairment, and neurodegeneration
• Protein aggregation is widespread, tissue-specific, and protein-specific in aging killifish (Chen et al, 2022)

Protein Quality Control

• Up to 30% of the proteome is translated and immediately degraded (Schubert et al, 2000)
• 85% of the proteome interacts with folding chaperones (To et al, 2022)
• Reduction in protein quality control creates "zombie proteins" that cannot be folded or degraded