α-Synuclein TransgenicDrosophilaAs a Model of Parkinson's Disease and Related Synucleinopathies

α-Synuclein (α-Syn) is a major component of protein inclusions known as Lewy bodies, which are hallmarks of synucleinopathies such as Parkinson's disease (PD). Theα-Syn gene is one of the familial PD-causing genes and is also associated with an increased risk of sporadic PD. Numerous studies usingα-Syn expressing transgenic animals have indicated thatα-Syn plays a critical role in the common pathogenesis of synucleinopathies.Drosophila melanogasterhas several advantages for modeling human neurodegenerative diseases and is widely used for studying their pathomechanisms and therapies. In fact,Drosophilamodels expressingα-Syn have already been established and proven to replicate several features of human PD. In this paper, we review the current research on synucleinopathies usingα-SynDrosophilamodels and, moreover, explore the possibilities of these models for comprehensive genetic analyses and large-scale drug screening towards elucidating the molecular pathogenesis and developing therapies for synucleinopathies.

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Copper(II)-induced self-oligomerization of α-synuclein

Biochemical Journal ◽

10.1042/bj3400821 ◽

1999 ◽

Vol 340 (3) ◽

pp. 821-828 ◽

Cited By ~ 142

Author(s):

Seung R. PAIK ◽

Hyun-Ju SHIN ◽

Ju-Hyun LEE ◽

Chung-Soon CHANG ◽

Jongsun KIM

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Metal Ion ◽

Senile Plaques ◽

Lewy Bodies ◽

Amyloid Β ◽

Coupling Reagents ◽

C Terminus ◽

Nucleation Centre ◽

The Common

α-Synuclein is a component of the abnormal protein depositions in senile plaques and Lewy bodies of Alzheimer's disease (AD) and Parkinson's disease respectively. The protein was suggested to provide a possible nucleation centre for plaque formation in AD via selective interaction with amyloid β/A4 protein (Aβ). We have shown previously that α-synuclein has experienced self-oligomerization when Aβ25-35 was present in an orientation-specific manner in the sequence. Here we examine this biochemically specific self-oligomerization with the use of various metals. Strikingly, copper(II) was the most effective metal ion affecting α-synuclein to form self-oligomers in the presence of coupling reagents such as dicyclohexylcarbodi-imide or N-(ethoxycarbonyl)-2-ethoxy-1,2-dihydroquinoline. The size distribution of the oligomers indicated that monomeric α-synuclein was oligomerized sequentially. The copper-induced oligomerization was shown to be suppressed as the acidic C-terminus of α-synuclein was truncated by treatment with endoproteinase Asp-N. In contrast, the Aβ25-35-induced oligomerizations of the intact and truncated forms of α-synuclein were not affected. This clearly indicated that the copper-induced oligomerization was dependent on the acidic C-terminal region and that its underlying biochemical mechanism was distinct from that of the Aβ25-35-induced oligomerization. Although the physiological or pathological relevance of the oligomerization remains currently elusive, the common outcome of α-synuclein on treatment with copper or Aβ25-35 might be useful in understanding neurodegenerative disorders in molecular terms. In addition, abnormal copper homoeostasis could be considered as one of the risk factors for the development of disorders such as AD or Parkinson's disease.

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Gut–Brain Axis: Potential Factors Involved in the Pathogenesis of Parkinson's Disease

Frontiers in Neurology ◽

10.3389/fneur.2020.00849 ◽

2020 ◽

Vol 11 ◽

Author(s):

Yin-Xia Chao ◽

Muhammad Yaaseen Gulam ◽

Nicholas Shyh Jenn Chia ◽

Lei Feng ◽

Olaf Rotzschke ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Large Scale ◽

Genetic Factors ◽

Dietary Factors ◽

Environmental Toxins ◽

Treatment Paradigm ◽

The Common ◽

Potential Factors ◽

Exact Relationship

Increasing evidence suggests an association between gastrointestinal (GI) disorders and susceptibility and progress of Parkinson's disease (PD). Gut–brain axis has been proposed to play important roles in the pathogenesis of PD, though the exact pathophysiologic mechanism has yet to be elucidated. Here, we discuss the common factors involved in both PD and GI disorders, including genes, altered gut microbiota, diet, environmental toxins, and altered mucosal immunity. Large-scale prospective clinical studies are needed to define the exact relationship between dietary factors, microbiome, and genetic factors in PD. Identification of early diagnostic markers and demonstration of the efficacy of diet modulation and regulation of gut microbiome through specific therapeutics can potentially change the treatment paradigm for PD.

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Drosophila melanogaster a versatile model of Parkinson’s Disease

CNS & Neurological Disorders - Drug Targets ◽

10.2174/1871527320666210208125912 ◽

2021 ◽

Vol 20 ◽

Author(s):

Falaq Naz ◽

Yasir Hasan Siddique

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Drosophila Melanogaster ◽

Lewy Bodies ◽

Substantia Nigra Pars Compacta ◽

Maintenance Cost ◽

The Novel ◽

Life Threatening ◽

Non Motor Symptoms ◽

The Brain

: Parkinson's Disease (PD) is one of the most prevalent, recurrent and life-threatening neurodegenerative disease. However, the precise mechanism underlying this disease is not yet clearly understood. For understanding the pathogenesis of PD, it is essential to identify the symptoms along with the novel biological markers and to develop strategies which could lead towards the development of effective therapy. PD is associated with Lewy bodies (LBs) formation and the loss of dopaminergic neurons in the substantia nigra pars compacta of mid brain region. For the improvement in treatment strategiesas well as understanding the pathophysiology of the PD in number ofanimal models have been introduced that can recapitulatethe pathophysiology, motor and non-motor symptoms of PD. In contrast to mammalian models like rodents, mice and monkey, Drosophila is easy to handle as well as it maintenance cost is low.Due to the anatomical differencesin the brain and other major organsof human and fly,the issues of standardizing the methods or experiments to analyze behavioral aspects (walking, writhing, eating and sleeping) are difficult in flies. Thepresent review highlights the studies carried out for PD since 2000, using Drosophila melanogaster.

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Contribution of rare homozygous and compound heterozygous VPS13C missense mutations to dementia with Lewy bodies and Parkinson’s disease

Acta Neuropathologica Communications ◽

10.1186/s40478-021-01121-w ◽

2021 ◽

Vol 9 (1) ◽

Author(s):

Stefanie Smolders ◽

◽

Stéphanie Philtjens ◽

David Crosiers ◽

Anne Sieben ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Early Onset ◽

Dementia With Lewy Bodies ◽

Lewy Bodies ◽

Lewy Body Disease ◽

Compound Heterozygous ◽

Missense Mutations ◽

Increased Risk ◽

Vacuolar Protein

AbstractDementia with Lewy bodies (DLB) and Parkinson’s disease (PD) are clinically, pathologically and etiologically disorders embedded in the Lewy body disease (LBD) continuum, characterized by neuronal α-synuclein pathology. Rare homozygous and compound heterozygous premature termination codon (PTC) mutations in the Vacuolar Protein Sorting 13 homolog C gene (VPS13C) are associated with early-onset recessive PD. We observed in two siblings with early-onset age (< 45) and autopsy confirmed DLB, compound heterozygous missense mutations in VPS13C, p.Trp395Cys and p.Ala444Pro, inherited from their healthy parents in a recessive manner. In lymphoblast cells of the index patient, the missense mutations reduced VPS13C expression by 90% (p = 0.0002). Subsequent, we performed targeted resequencing of VPS13C in 844 LBD patients and 664 control persons. Using the optimized sequence kernel association test, we obtained a significant association (p = 0.0233) of rare VPS13C genetic variants (minor allele frequency ≤ 1%) with LBD. Among the LBD patients, we identified one patient with homozygous missense mutations and three with compound heterozygous missense mutations in trans position, indicative for recessive inheritance. In four patients with compound heterozygous mutations, we were unable to determine trans position. The frequency of LBD patient carriers of proven recessive compound heterozygous missense mutations is 0.59% (5/844). In autopsy brain tissue of two unrelated LBD patients, the recessive compound heterozygous missense mutations reduced VPS13C expression. Overexpressing of wild type or mutant VPS13C in HeLa or SH-SY5Y cells, demonstrated that the mutations p.Trp395Cys or p.Ala444Pro, abolish the endosomal/lysosomal localization of VPS13C. Overall, our data indicate that rare missense mutations in VPS13C are associated with LBD and recessive compound heterozygous missense mutations might have variable effects on the expression and functioning of VPS13C. We conclude that comparable to the recessive inherited PTC mutations in VPS13C, combinations of rare recessive compound heterozygous missense mutations reduce VPS13C expression and contribute to increased risk of LBD.

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Dementia in Parkinson’s disease

New Oxford Textbook of Psychiatry ◽

10.1093/med/9780198713005.003.0044 ◽

2020 ◽

pp. 435-447

Author(s):

Michele Hu ◽

Fahd Baig

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Lewy Bodies ◽

Lewy Body Dementia ◽

Nursing Home Admission ◽

Patient Specific ◽

Future Research ◽

The United Kingdom ◽

Increased Risk ◽

Therapeutic Needs

Lewy body dementia includes Parkinson’s disease dementia (PDD) and dementia with Lewy bodies (DLB), and is the second most common form of dementia after Alzheimer’s disease (AD). Both conditions share significant phenotypic and pathological signatures but differ in terms of whether Parkinsonian symptoms appear first (PDD) or after/the same time as cognitive symptoms (DLB). In the United Kingdom, over 100,000 people are affected, with numbers predicted to double by 2050. Average care costs per patient are more than double those of AD, reflecting the associated multi-morbidity and unmet therapeutic needs. PDD has a long-term cumulative prevalence of 80% and major consequences for independence, nursing home admission, psychiatric comorbidity, caregiver burden, and mortality. Consequently, there is interest in a potential transition stage—Parkinson’s disease with mild cognitive impairment (PD-MCI)—to identify those at increased risk for PDD, to facilitate intervention studies. Advances in both symptomatic and disease-modifying treatments have so far been limited. Future research must address patient-specific factors influencing variability in treatment response and progression to be effective.

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Balancing mTOR Signaling and Autophagy in the Treatment of Parkinson’s Disease

International Journal of Molecular Sciences ◽

10.3390/ijms20030728 ◽

2019 ◽

Vol 20 (3) ◽

pp. 728 ◽

Cited By ~ 35

Author(s):

Zhou Zhu ◽

Chuanbin Yang ◽

Ashok Iyaswamy ◽

Senthilkumar Krishnamoorthi ◽

Sravan Gopalkrishnashetty Sreenivasmurthy ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Critical Role ◽

Mammalian Target Of Rapamycin ◽

Lewy Bodies ◽

Mtor Signaling ◽

Substantia Nigra Pars Compacta ◽

Future Drug ◽

Vacuolar Protein ◽

Dopaminergic Neuron Loss

The mammalian target of rapamycin (mTOR) signaling pathway plays a critical role in regulating cell growth, proliferation, and life span. mTOR signaling is a central regulator of autophagy by modulating multiple aspects of the autophagy process, such as initiation, process, and termination through controlling the activity of the unc51-like kinase 1 (ULK1) complex and vacuolar protein sorting 34 (VPS34) complex, and the intracellular distribution of TFEB/TFE3 and proto-lysosome tubule reformation. Parkinson’s disease (PD) is a serious, common neurodegenerative disease characterized by dopaminergic neuron loss in the substantia nigra pars compacta (SNpc) and the accumulation of Lewy bodies. An increasing amount of evidence indicates that mTOR and autophagy are critical for the pathogenesis of PD. In this review, we will summarize recent advances regarding the roles of mTOR and autophagy in PD pathogenesis and treatment. Further characterizing the dysregulation of mTOR pathway and the clinical translation of mTOR modulators in PD may offer exciting new avenues for future drug development.

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