Dementia with Lewy bodies—associated ß-synuclein mutations V70M and P123H cause mutation-specific neuropathological lesions

Abstract

ß-Synuclein (ß-Syn) has long been considered to be an attenuator for the neuropathological effects caused by the Parkinson’s disease-related α-Synuclein (α-Syn) protein. However, recent studies demonstrated that overabundant ß-Syn can form aggregates and induce neurodegeneration in CNS neurons in vitro and in vivo, albeit at a slower pace as compared to α-Syn. Here we demonstrate that ß-Syn mutants V70M, detected in a sporadic case of Dementia with Lewy Bodies (DLB), and P123H, detected in a familial case of DLB, robustly aggravate the neurotoxic potential of ß-Syn. Intriguingly, the two mutations trigger mutually exclusive pathways. ß-Syn V70M enhances morphological mitochondrial deterioration and degeneration of dopaminergic and non-dopaminergic neurons, but has no influence on neuronal network activity. Conversely, ß-Syn P123H silences neuronal network activity, but does not aggravate neurodegeneration. ß-Syn WT, V70M and P123H formed proteinase K (PK) resistant intracellular fibrils within neurons, albeit with less stable C-termini as compared to α-Syn. Under cell free conditions, ß-Syn V70M demonstrated a much slower pace of fibril formation as compared to WT ß-Syn, and P123H fibrils present with a unique phenotype characterized by large numbers of short, truncated fibrils. Thus, it is possible that V70M and P123H cause structural alterations in ß-Syn, that are linked to their distinct neuropathological profiles. The extent of the lesions caused by these neuropathological profiles is almost identical to that of overabundant α-Syn, and thus likely to be directly involved into etiology of DLB. Over all, this study provides insights into distinct disease mechanisms caused by mutations of ß-Syn.

Synaptic vesicle binding of α-synuclein is modulated by β- and γ-synucleins

“…In addition to identifying a physiological role for βSyn and γSyn, our findings may also have implications for the contributions of βSyn and γSyn to disease. βSyn and γSyn have links to several neurodegenerative diseases ( Galvin et al, 1999 , 2000 ; Nguyen et al, 2011 ; Ninkina et al, 2009 ; Nishioka et al, 2010 ; Peters et al, 2012 ; Surgucheva et al, 2002 ), and missense mutations in βSyn, as well as βSyn or γSyn overexpression, cause neurodegeneration ( Fujita et al, 2020 ; Ninkina et al, 2009 ; Ohtake et al, 2004 ; Peters et al, 2012 ; Psol et al, 2021 ; Taschenberger et al, 2013 ). We and others have previously shown that lack of SNARE chaperoning by αSyn or the CSPα chaperone complex causes progressive neuropathology ( Burré et al, 2010 , 2012 , 2015 ; Greten-Harrison et al, 2010 ; Sharma et al, 2011 , 2012 ).…”

α-Synuclein Impacts on Intrinsic Neuronal Network Activity Through Reduced Levels of Cyclic AMP and Diminished Numbers of Active Presynaptic Terminals

“…Neuron/glia co-cultures develop a fully matured neuronal network with robust intrinsic activity (Murphy et al, 1992 ), characterized as network bursts. Such cultures can be readily used to study the impact of synucleins on their network activity, in terms of frequency of network bursts and percentages of neurons contributing to network bursts (Tolo et al, 2018 ; Psol et al, 2021 ). Both parameters can be recorded with high accuracy due to the 2D-arrangement of cultured neurons, allowing to assess all cells contributing to network activity simultaneously.…”

Neurogenesis-An Overview

“…Neuronal differentiation is also observed to be altered in human induced pluripotent stem cells (iPSC) derived dopaminergic neurons in the context of PD [25,26] also observed when glutamatergic neurons were transdifferentiated into dopaminergic neurons [27,28]. Mouse models of PD showed there is less amount of neurogenesis in older mice [29], as well as different protein accumulation was significantly toxic to the neurons [30]. It is, however, clear if this strategy is to be considered as a therapy approach, more work needs to be performed to determine whether adult neurogenesis is affected in neurodegenerative disorders, till then more emphasis needs to be given to identifying biomarkers to predict the disease at an earlier stage [31] or use the differentiated neurons as tools to test different drug candidates [32], as it has been demonstrated that neurons are affected differently [33].…”