![]() The 2N/4R τ isoform is 441 amino acids long and is composed of an N-terminal region, a proline-rich region, an MTBD with four MT binding repeats (R1–R4), and a C-terminal region. Schematic of 2N/4R τ and some of the major proteolytic cleavage sites Frontotemporal dementia with parkinsonism linked to chromosome 17 with τ inclusions (FTDP-17t) is caused by missense, silent or intronic MAPT mutations, establishing a direct causal role of τ in neurodegeneration. Hyperphosphorylated τ is the major component of insoluble pathological inclusions found in many tauopathies including, AD, frontotemporal dementia (FTD), progressive supranuclear palsy (PSP), corticobasal degeneration, and chronic traumatic encephalopathy (CTE). In the human central nervous system, τ can be alternatively spliced into six isoforms, based on the presence or absence of exons, 2, 3, and 10, and are grouped into 3R or 4R isoforms, which contain three or four MT-associated binding repeats, respectively. τ's protein structure is composed of an amino (N)-terminal region, a proline-rich region, a microtubule-binding domain (MTBD), and a carboxy (C)-terminal region ( Figure 1). Microtubule-associated protein τ is encoded in the MAPT gene and binds to microtubules (MTs), promoting their assembly and stability. τ protein and disease-associated proteolytic fragments Here, we present the concept that similarities in the proteolysis of τ protein and αSyn could be closely linked and significantly contribute to the development of neurodegeneration in a variety of different diseases. In vitro studies and experimental models have demonstrated that αSyn can initiate τ aggregation, and that both types of protein aggregation can be synergistic. For example, in many neurodegenerative diseases, pathological inclusions containing τ and αSyn often present concurrently and even co-localize within the same cells. Increasing evidence shows that τ and αSyn can lead to the formation of hybrid fibrils and aggregates. Both τ and αSyn can undergo extensive post-translational modifications that may promote their prion-like seeding potency and toxic spread. Prion-like conformational mechanisms have been implicated in the propagation of τ and αSyn protein aggregates associated with the insidious nature of neurodegenerative diseases. The progressive accumulation of τ and αSyn-laden pathological inclusions each defines a spectrum of neurodegenerative diseases however, the affected brain regions, the involved neuronal populations and contribution of other brain cells, such as astrocytes and oligodendrocytes, can be disease-specific. Natively, both proteins are intrinsically disordered and can adopt multiple conformations. Τ and α-synuclein (αSyn) form toxic brain inclusions as either neurofibrillary tangles (NFTs) in Alzheimer's disease (AD) or Lewy bodies (LBs) in Parkinson's disease (PD), respectively. The future development of new tools to detect specific τ and αSyn abnormal cleavage products in peripheral biofluids could be useful biomarkers and better understand of the role of unique proteolytic activities could yield therapeutic interventions. The accumulation of some of these cleavage products can further potentiate the progression of protein aggregation transmission and lead to their accumulation in peripheral biofluids such as cerebrospinal fluid (CSF) and blood. The initiating events in most sporadic neurodegenerative diseases are still unclear but growing evidence suggests that the aberrant proteolytic cleavage of τ and αSyn results in products that can be toxic and/or initiate aggregation that can further spread by a prion-like mechanism. The aggregation of both proteins is clearly associated with neurodegeneration and the deleterious properties of each protein is further supported by mutations in each gene ( MAPT and SNCA, respectively) resulting in disease. CNS pathological inclusions comprising τ or α-synuclein (αSyn) define a spectrum of neurodegenerative diseases, and these can often present concurrently in the same individuals.
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