Update on the association between alpha‐synuclein and tau with mitochondrial dysfunction: Implications for Parkinson's disease

Feng, Sitong; Wang, Zhenzhen; Yuan, Yu‐He; Sun, Haixiang; Chen, Nai‐Hong; Zhang, Yi

doi:10.1111/ejn.14699

Cited by 30 publications

(23 citation statements)

References 162 publications

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“…Tau pathology, which is believed to be caused by hyperphosphorylation of microtubule-associated protein tau, is observed in patients affected with sporadic or familial PD 42,43 . A similar protein expression of cytosolic tau was observed in SN of WT and VPS35 D620N/+ mice aged 12 or 16 months (Fig.…”

Section: Resultsmentioning

confidence: 99%

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(D620N) VPS35 causes the impairment of Wnt/β-catenin signaling cascade and mitochondrial dysfunction in a PARK17 knockin mouse model

et al. 2020

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Patients with familial type 17 of Parkinson’s disease (PARK17) manifest autosomal dominant pattern and late-onset parkinsonian syndromes. Heterozygous (D620N) mutation of vacuolar protein sorting 35 (VPS35) is genetic cause of PARK17. We prepared heterozygous VPS35D620N/+ knockin mouse, which is an ideal animal model of (D620N) VPS35-induced autosomal dominant PARK17. Late-onset loss of substantia nigra pars compacta (SNpc) dopaminergic (DAergic) neurons and motor deficits of Parkinson’s disease were found in 16-month-old VPS35D620N/+ mice. Normal function of VPS35-containing retromer is needed for activity of Wnt/β-catenin cascade, which participates in protection and survival of SNpc DAergic neurons. It was hypothesized that (D620N) VPS35 mutation causes the malfunction of VPS35 and resulting impaired activity of Wnt/β-catenin pathway. Protein levels of Wnt1 and nuclear β-catenin were reduced in SN of 16-month-old VPS35D620N/+ knockin mice. Downregulated protein expression of survivin, which is a target gene of nuclear β-catenin, and upregulated protein levels of active caspase-8 and active caspase-9 were observed in SN of VPS35D620N/+ mice at age of 16 months. VPS35 is involved in controlling morphology and function of mitochondria. Impaired function of VPS35 caused by (D620N) mutation could lead to abnormal morphology and malfunction of mitochondria. A significant decrease in mitochondrial size and resulting mitochondrial fragmentation was found in tyrosine hydroxylase-positive and neuromelanin-positive SNpc DAergic neurons of 16-month-old VPS35D620N/+ mice. Mitochondrial complex I activity or complex IV activity was reduced in SN of 16-month-old VPS35D620N/+ mice. Increased level of mitochondrial ROS and oxidative stress were found in SN of 16-month-old VPS35D620N/+ mice. Levels of cytosolic cytochrome c and active caspase-3 were increased in SN of VPS35D620N/+ mice aged 16 months. Our results suggest that PARK17 mutant (D620N) VPS35 impairs activity of Wnt/β-catenin signaling pathway and causes abnormal morphology and dysfunction of mitochondria, which could lead to neurodegeneration of SNpc DAergic cells.

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Section: Resultsmentioning

confidence: 99%

“…Accumulation of hyperphosphorylated microtubuleassociated protein tau could cause tau pathology, which is observed in patients affected with sporadic or hereditary PD 42,43 . Interestingly, increased protein level of phosphotau Ser202/Thr205 was found in SN of VPS35 D620N/+ mice aged 16 months.…”

Section: Discussionmentioning

confidence: 99%

(D620N) VPS35 causes the impairment of Wnt/β-catenin signaling cascade and mitochondrial dysfunction in a PARK17 knockin mouse model

et al. 2020

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“…From a functional point of view, tau and αSyn share a significant role in cell trafficking and synaptic functions at the axonal level and both play a role in regulating mitochondrial homeostasis. In fact, pathologic αSyn and tau cause mitochondrial dysfunction and oxidative stress, and tau aggregates amplifies the neurotoxic effects on mitochondria by interacting with αSyn; on the other hand, oxidative stress caused by mitochondrial impairment induces aggregation of both αSyn and tau [ 278 ].…”

Section: Tau and Alpha Synuclein Commonalities And Diversitiesmentioning

confidence: 99%

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

Vacchi

Kaelin‐Lang

Melli

2020

IJMS

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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.

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“…The α-Syn protein plays critical roles in both sporadic and familial PD as (1) mutations or multiplications of the SNCA gene cause autosomal-dominant PD [25], (2) genome-wide association studies show a correlation between single-nucleotide polymorphisms in the SNCA locus and the risk of developing sporadic PD [26,27], (3) levels of phosphorylated α-Syn are increased in post-mortem brains of PD patients and patient-derived dopaminergic neurons [28], (4) DA neurons that lack α-Syn are protected in neurotoxin and genetic models of PD [29][30][31]. Additionally, α-Syn has been shown to interact with several proteins implicated in PD and other neurodegenerative disorders, including tau [32,33], LRKK2 [34], Fyn [35], parkin [36], and DJ-1 [37].…”

Section: Synucleinopathiesmentioning

confidence: 99%

Roles for α-Synuclein in Gene Expression

Somayaji

Lanseur

Choi

et al. 2021

Genes

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α-Synuclein (α-Syn) is a small cytosolic protein associated with a range of cellular compartments, including synaptic vesicles, the nucleus, mitochondria, endoplasmic reticulum, Golgi apparatus, and lysosomes. In addition to its physiological role in regulating presynaptic function, the protein plays a central role in both sporadic and familial Parkinson’s disease (PD) via a gain-of-function mechanism. Because of this, several recent strategies propose to decrease α-Syn levels in PD patients. While these therapies may offer breakthroughs in PD management, the normal functions of α-Syn and potential side effects of its depletion require careful evaluation. Here, we review recent evidence on physiological and pathological roles of α-Syn in regulating activity-dependent signal transduction and gene expression pathways that play fundamental role in synaptic plasticity.

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Update on the association between alpha‐synuclein and tau with mitochondrial dysfunction: Implications for Parkinson's disease

Cited by 30 publications

References 162 publications

(D620N) VPS35 causes the impairment of Wnt/β-catenin signaling cascade and mitochondrial dysfunction in a PARK17 knockin mouse model

(D620N) VPS35 causes the impairment of Wnt/β-catenin signaling cascade and mitochondrial dysfunction in a PARK17 knockin mouse model

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

Roles for α-Synuclein in Gene Expression

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