Wolframin is a novel regulator of tau pathology and neurodegeneration

Abstract

Selective neuronal vulnerability to protein aggregation is found in many neurodegenerative diseases including Alzheimer's disease (AD). Understanding the molecular origins of this selective vulnerability is therefore of fundamental importance. Tau protein aggregates have been found in manuscriptClick here to access/download;manuscript;Manuscript_Final submission.docx Click here to view linked References Wolframin (WFS1)-expressing excitatory neurons in the entorhinal cortex, one of the earliest affected regions in AD. The role of WFS1 in Tauopathies and its levels in tau pathology-associated neurodegeneration, however, is largely unknown. Here we report WFS1 deficiency is associated with increased tau pathology and neurodegeneration, whereas overexpression of WFS1 reduces those changes. We also find that WFS1 interacts with tau protein and controls the susceptibility to tau pathology. Furthermore, chronic ER stress-and autophagy-lysosome pathway (ALP)associated genes are enriched in WFS1-high excitatory neurons in human AD at early Braak stages.The protein levels of ER stress-and autophagy-lysosome pathway (ALP)-associated proteins are changed in tau transgenic mice with WFS1 deficiency, while overexpression of WFS1 reverses those changes. This work demonstrates a possible role for WFS1 in the regulation of tau pathology and neurodegeneration via chronic ER stress and the downstream ALP. Our findings provide insights into mechanisms that underpin selective neuronal vulnerability, and for developing new therapeutics to protect vulnerable neurons in AD.

Spread of pathological human Tau from neurons to oligodendrocytes and loss of high-firing pyramidal neurons in ageing mice

“…The apparent downregulation of the transmembrane glycoprotein Wfs1 in pTau+ pyramidal cells could be related to its role in regulating degradation of misfolded proteins in the endoplasmic reticulum, highlighting susceptibility to neurodegeneration. 18 Oligodendrocytes also became pTau+ and were associated with pTau+ white matter tracts. We suggest the extensive Tau pathology in the hippocampal formation and loss of higher firing ProS cells contributed to specific deficits in short-term familiarity.…”

“…2c, S3a), suggesting that pTau affects Wfs1 levels. 17,18 The upper, compact sublayer of stratum pyramidale (SP) primarily consists of calbindin immunopositive (CB+) neurons, and the lower sublayer neurons are mostly CB immunonegative (CB−, lacking detectable levels of CB). 16,19 Interestingly, the majority of pTau+ CA1 SP neurons were found in the deep sublayer and were CB− (95 ± 6 % for n=3 young mice < 8 mo, n=3/52 CB+ pTau+ cells; 85 ± 5 % for n=3 ageing mice 8-14 mo, n=9/60 CB+ pTau+ cells; 79 ± 11 % for n=5 aged mice 16-23 mo, n=11/59 CB+ pTau+ cells; Fig.…”

NCS1 overexpression restored mitochondrial activity and behavioral alterations in a zebrafish model of Wolfram syndrome

“…Interestingly, NCS1 exerts similar functions as WFS1: both proteins regulate cytosolic Ca 2+ levels and IP3R-dependent ER-Ca 2+ release 20 , 32 , 33 , 34 modulate neuronal morphology and neurodevelopment, 49 , 50 mediate neuroprotection, 51 and have been implicated in neurodegenerative diseases and psychiatric disorders beyond WS. 52 , 53 , 54 In human fibroblasts, NCS1 knockdown impaired Ca 2+ homeostasis and mitochondrial function, demonstrating that NCS1 modulated [Ca 2+ ] m uptake and could be a target to maintain mitochondrial function and MAM integrity. In addition, the overexpression of NCS1 in patient fibroblasts restored the defective mitochondrial phenotype of WFS1-deficient cells.…”

Dysregulated Ca2+ Homeostasis as a Central Theme in Neurodegeneration: Lessons from Alzheimer’s Disease and Wolfram Syndrome

“…The hyperphosphorylated tau forming neurofibrillary tangles is a major hallmark of AD and is serving as a potential therapeutic target [ 183 ]. Recently, Chen et al described a novel function for Wfs1 in the development and progression of tau pathology [ 184 ]. The Wfs1 can interact with tau protein and affect its aggregation and propagation.…”

“…Moreover, increased Wfs1 reduced tau pathology and neurodegeneration in PS19 mice, a widely used tauopathy model which resembles AD-like pathology. On the other hand, Wfs1 deficiency increased the pathological tau and apoptosis, and impaired the spatial learning and memory in PS19 mice [ 184 ].…”