Despite the vast differences in symptoms experienced by patients with neurodegenerative diseases (ND), their pathology shares similar features at a molecular level. Most notably, many ND involve an accumulation of misfolded proteins within specific regions in the brain. While the processes involved in the genesis and accumulation of misfolded proteins were initially thought to be distinct for each disease, advancements in technology have allowed scientists to recognize parallels and similarities that were previously overlooked. New discussions in the scientific literature propose several proteins as key players in the development of ND. Understanding their role might provide invaluable insight into therapeutic advancements for ND moving forward. Here, we discuss those proteins of interest, as well as the leading hypotheses guiding current research projects.
The neural proteome — the proteins expressed throughout the nervous system — consists of roughly 15,000 proteins that must be precisely produced, folded, and regulated to maintain proper function in the body. Chaperone proteins typically bind to new proteins, support proper folding, quality check once folding is completed, and send any misfolded proteins to be either re-folded, degraded, or sequestered. However, factors such as cellular aging can promote misfolding and escape from these quality control systems [Marsh 2019].
Heat Shock Proteins (HSP) are a major subset of chaperone proteins that are typically highly conserved among species and, as their name suggests, activated in response to elevated temperatures [Lindquist 1988]. HSP are primarily involved in the prevention of protein aggregation. Scientific reports have linked mutations in key HSP to ND like Parkinson’s Disease (PD) and Amyotrophic Lateral Sclerosis (ALS). Additionally, knockout studies of well-conserved chaperone Hsp110, in particular, have led to the appearance of two major proteins associated with Alzheimer’s Disease (AD): accumulation of hyperphosphorylated tau — which has been extensively linked to degeneration — and amyloid-beta (Aβ). Other studies have identified links between knockouts of Hsp70 and increased physical and behavioral biomarkers for Huntington’s Disease.
Another protein of interest is DJ-1 — also known as Parkinson disease protein 7 — which is thought to be a chaperone protein that modulates toxicity and misfolding of α-synuclein in certain forms of PD. While the mechanism hasn’t been fully elucidated, α-synuclein is hypothesized to be involved in the pathogenic process underlying PD and has also been implicated in AD and Dementia with Lewy Bodies (DLB). Interestingly, preliminary studies have shown that DJ-1 might also be linked to the formation of tau inclusions. Though further studies are needed, DJ-1 appears to be a promising biomarker and potential therapeutic target for PD and might also shed light on a broader range of ND [Repici et al 2019].
Other studies have shown that a protein called Apolipoprotein E (APOE) — which is abundantly expressed throughout the central nervous system — is associated with dementia. In particular, polymorphism in the gene encoding APOE is a major genetic risk determinant for late-onset AD. There is increasing evidence in the literature that one of the allelic variants of APOE, APOE3*ɛ4, promotes aggregation of Aβ. Studies suggest this variant might also directly increase the risk of TDP-43 pathology, which is the main aggregating protein in ALS and Frontotemporal Dementias. Additionally, new studies have explored the association of APOE with tau-mediated degeneration, as well as the risk of developing DLB and PD.
Ultimately, despite the complexity of these molecular interactions and pathways, one thing remains clear: protein misfolding underpins the pathogenesis of many ND. However, the genetic basis, the specific proteins implicated, and aggregates formed varies between diseases. Though there is some debate, an emerging hypothesis in the field is that of protein propagation. More specifically, proteins tau, TDP-43, and α-synuclein have been shown to exhibit self-perpetuated aggregation in a manner similar to that of prions. While the nuances of this hypothesis have yet to be completely explored, sufficient evidence exists to pursue the clearance of these protein aggregates as a therapeutic avenue for ND treatment. Furthermore, future studies are likely to focus more on protein expression and post-translational modification of these proteins, rather than genetic sequence analysis alone [Marsh 2019].
Exploring the molecular mechanisms of the proteins highlighted here will deepen our understanding of how ND develop. And with this enhanced knowledge, we will be closer to developing more effective therapies for a wide range of ND.