Tau and Alpha Synuclein Synergistic Effect in Neurodegenerative Diseases: When the Periphery Is the Core

Abstract

In neuronal cells, tau is a microtubule-associated protein placed in axons and alpha synuclein is enriched at presynaptic terminals. They display a propensity to form pathologic aggregates, which are considered the underlying cause of Alzheimer's and Parkinson's diseases. Their functional impairment induces loss of axonal transport, synaptic and mitochondrial disarray, leading to a "dying back" pattern of degeneration, which starts at the periphery of cells. In addition, pathologic spreading of alpha-synuclein from the peripheral nervous system to the brain through anatomical connectivity has been demonstrated for Parkinson's disease. Thus, examination of the extent and types of tau and alpha-synuclein in peripheral tissues and their relation to brain neurodegenerative diseases is of relevance since it may provide insights into patterns of protein aggregation and neurodegeneration. Moreover, peripheral nervous tissues are easily accessible in-vivo and can play a relevant role in the early diagnosis of these conditions. Up-to-date investigations of tau species in peripheral tissues are scant and have mainly been restricted to rodents, whereas, more evidence is available on alpha synuclein in peripheral tissues. Here we aim to review the literature on the functional role of tau and alpha synuclein in physiological conditions and disease at the axonal level, their distribution in peripheral tissues, and discuss possible commonalities/diversities as well as their interaction in proteinopathies.

Keywords: Alzheimer’s disease; Big tau; Parkinson’s disease; alpha-synuclein; axonal degeneration; intrinsically disordered proteins; neurodegenerative disorders; peripheral nervous system; proteinopathies; tau.

Figure 1

Gene, isoforms and functional domains of Tau and αSyn proteins. (a) Schematic representation of human MAPT gene present on chromosome 17. Its sixteen exons, through alternative splicing of exons 2, 3, and 10 (green), can generate 6 isoforms. Moreover, in peripheral tissue, the addition of exon 4a (light blue) generates the high molecular weight protein: Big Tau. The protein can be subdivided into 4 functional domains: N-terminal region, Proline rich region, Tubulin binding region, and C-terminal region. (b) Schematic representation of the SNCA gene present on chromosome 4. Exons 1a and 1b (red) are not translated. αSyn protein can be subdivided into 3 functional domains: amphipathic region, hydrophobic non-amyloid component (NAC) domain, and acidic tail.

Figure 2

Tau protein in physiology and pathology. On the left, schematic representation of physiological tau functions at postsynaptic, axonal, and presynaptic level. On the right, pathological effects of abnormal (oligomeric and neurofibrillary tangles) tau in the three cellular compartments.

Figure 3

αSyn protein in physiology and pathology. On the left, schematic representation of physiological αSyn functions at the postsynaptic, axonal, and presynaptic level. On the right, the pathological effects of abnormal (oligomeric and protofibrillary) αSyn in the three cellular compartments. SERT:serotonin; NET: norepinephrine; DAT: dopamine transporter; VMAT2: vesicular monoamine transporter 2.