Neurodegenerative diseases manifest as the progressive dysfunction and loss of neurons, which is frequently accompanied by formation of misfolded protein deposits in the brain. Classification of neurodegenerative diseases is based on clinical symptoms, which depend on the anatomical region affected by neuronal dysfunction, the identity of misfolded proteins and cellular and subcellular pathology.
In Alzheimer’s disease (AD), beta-amyloid protein (APP) deposits form in the extracellular space, where they can make plaques, while abnormally phosphorylated tau protein (MAPT) accumulates in neuronal cells.
Beside AD, neuronal and/or glial inclusions of hyperphosphorylated tau are also found in Pick disease (PiD), neurofibrillary tangle-dementia (NFT), primary age-related tauopathy (PART), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), argyrophilic grain disease (AGD) and globular glial tauopathies (GGT).
In prion disease, such as Creutzfeldt-Jakob disease, deposits of PrP protein are formed mostly in the extracellular and presynaptic space. PrP deposits in neuronal cell bodies are mainly confined to endosomes and lysosomes, which is attributed to neuronal uptake of pathological proteins and intercellular prion spreading.
In Parkinson disease (PD) and dementia with Lewy bodies (DLB), deposits of alpha-synuclein (SNCA) are formed in the cytoplasm of neuronal cell bodies and neurites. In multiple system atrophy (MSA), deposits of alpha-synuclein form in the cytoplasm of glial cells (Papp-Lantos bodies).
Amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) are characterized by ubiquitin-positive cytoplasmic inclusions of TAR DNA-binding protein 43 (TARDBP, commonly known as TDP-43), a protein that normally localizes to the nucleus. Pathological TDP-43 inclusions have been associated with the TDP-43 gene mutations, as well as mutations in several other genes, including C9orf72, GRN, VCP, SQSTM1, DCTN1 and OPTN. TDP-43 inclusions have also been reported in AD, DLB, hippocampal sclerosis (HS) and chronic traumatic encephalopathy.
FUS protein-positive inclusion bodies are found in familial ALS, caused by mutations in the FUS gene, as well as in a small subgroup of FTLD-related diseases. FUS-positive inclusions may be accompanied by FET protein-positive inclusions.
For a detailed review of molecular pathology of neurodegenerative diseases, please refer to Kovacs 2016.
Within this broad domain, the process by which APP-triggered deregulation of CDK5 (cyclin-dependent kinase 5) triggers multiple neurodegenerative pathways associated with Alzheimer's disease has been annotated.