Proteinopathies refer to a group of diseases in which the structure of certain proteins is abnormal, thereby disrupting cellular function. , tissues and organs of the body. Proteins usually fail to fold into their normal conformation; in this misfolded state, proteins may somehow become toxic (toxic gain of function), or they may lose their normal function.
In the case of Alzheimer\’s disease, peptide amyloid beta (Aβ) is responsible for the protein disease, while α-synuclein plays a similar role in Parkinson\’s disease. The toxic effects of these protein oligomers or aggregates on the different functions of organelles define the term proteotoxicity, but even the monomeric forms of some of these proteins may be toxic in excess presence.
In terms of molecular pathogenesis, these two diseases have significant commonalities, with proteinopathy (abnormal accumulation of misfolded proteins), mitochondrial dysfunction and oxidative stress being the main features of both diseases. These three mechanisms of damage work in concert and reinforce each other, thus driving the aging brain pathology of both diseases.
The accumulation of specific toxic proteins may be due to transcriptional activation or translation enhancement of specific mRNAs or impaired proteasomal or lysosomal pathways leading to reduced protein degradation rates. Redox reactions and kinase mechanisms may lead to protein accumulation during post-translational modifications. In turn these proteins may also enable enhanced oxidative stress. Aggregation or oligomerization of proteins – even monomers of amyloid β or α-synuclein – can lead to various mitochondrial damages such as impaired bioenergetics, altered fusion/fission and impaired mitochondrial autophagy. In turn, excess reactive oxygen species may be generated , which triggers the cell death pathway.
For Alzheimer\’s disease, toxic proteins deposited outside brain cells as amyloid and neuritis plaques are called β-amyloid peptides (specifically Aβ42 and Aβ40 peptides), and they are derived from a precursor called amyloid precursor protein (APP) through the sequential action of two proteases. These two proteases, β(BACE1) and γ-secretase, cleave the peptides from APP. Oxidative stress leads to increased expression of APP and BACE1, resulting in the accumulation of Aβ42. Clearance of Aβ42 in the brain is also impeded by oxidative stress. On the other hand, multiple interactions of Aβ42 with mitochondria, microglia, and metal ions lead to further oxidative stress.
Excess α-synuclein accumulation in PD brain occurs through reduced degradation, increased SNCA transcription, and iron/IRE-regulated post-transcriptional mechanisms. α-synuclein (monomers and oligomers) interacts with mitochondria in a variety of ways, leading to organelle dysfunction and increased ROS production. Iron and DA oxidation products contribute to oxidative stress in the PD brain, which is further enhanced by iron-α-synuclein interactions.
Both Alzheimer\’s disease and Parkinson\’s disease eventually lead to programmed cell death of neurons. Alzheimer\’s disease symptoms are progressive dementia and deficits in multiple cognitive domains. Parkinson\’s disease manifests as a triad of motor bradykinesia, muscle tonus and resting tremor. With increasing time, a variety of secondary symptoms can develop.
