The Parkinson Disease gene SNCA: Evolutionary and structural insights with pathological implication

Siddiqui, Irum Javaid; Pervaiz, Nashaiman; Abbasi, Amir Ali

doi:10.1038/srep24475

Cited by 143 publications

(106 citation statements)

References 55 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Mutations of SYN are highly clustered between residues 18-53, in the lipid-binding N-terminal region of the protein. A comparative sequence and structural analysis suggested that the 32-58 region of SYN is critical for the stability and the secondary structure of the protein [43]. This is consistent with another study, in which predominantly the 39-45 aa segment, among others, was proposed to be involved in the membrane penetration [44].…”

Section: Syn: the Old Hallmark Of Parkinsonismsupporting

confidence: 86%

Pharmacological targeting of α‐synuclein and TPPP/p25 in Parkinson's disease: challenges and opportunities in a Nutshell

Oláh

Ovádi

2019

FEBS Letters

View full text Add to dashboard Cite

With the aging of population, neurological disorders, and especially disorders involving defects in protein conformation (also known as proteopathies) pose a serious socio‐economic problem. So far there is no effective treatment for most proteopathies, including Parkinson's disease (PD). The mechanism underlying PD pathogenesis is largely unknown, and the hallmark proteins, α‐synuclein (SYN) and tubulin polymerization promoting protein (TPPP/p25) are challenging drug targets. These proteins are intrinsically disordered with high conformational plasticity, and have diverse physiological and pathological functions. In the healthy brain, SYN and TPPP/p25 occur in neurons and oligodendrocytes, respectively; however, in PD and multiple system atrophy, they are co‐enriched and co‐localized in both cell types, thereby marking pathogenesis. Although large inclusions appear at a late disease stage, small, soluble assemblies of SYN promoted by TPPP/p25 are pathogenic. In the light of these issues, we established a new innovative strategy for the validation of a specific drug target based upon the identification of contact surfaces of the pathological SYN‐TPPP/p25 complex that may lead to the development of peptidomimetic foldamers suitable for pharmaceutical intervention.

show abstract

Section: Syn: the Old Hallmark Of Parkinsonismsupporting

confidence: 86%

Pharmacological targeting of α‐synuclein and TPPP/p25 in Parkinson's disease: challenges and opportunities in a Nutshell

Oláh

Ovádi

2019

FEBS Letters

View full text Add to dashboard Cite

show abstract

“…Parkinson's disease is characterized with selective loss of dopaminergic (DA) neurons in the substantia nigra and a deficiency of dopamine in the striatum [2][3][4][5]. The precise etiology of Parkinson's disease remains unclear.…”

Section: Introductionmentioning

confidence: 99%

Involvement of microRNA-135a-5p in the Protective Effects of Hydrogen Sulfide Against Parkinson's Disease

Liu

Liao

Quan

et al. 2016

Cell Physiol Biochem

View full text Add to dashboard Cite

Background/Aims: Development of effective therapeutic drugs for Parkinson's disease is in great need. During the progression of Parkinson's disease, Rho-associated protein kinase 2 (ROCK2) is activated to promote neurodegeneration. Hydrogen sulfide (H₂S) has a neuroprotective effect during the neural injury of Parkinson's disease. However, the mechanisms that underlie the effects of ROCK2 and H₂S remain ill-defined. In the current study, we addressed these questions. Methods: We used a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced mouse subacute model of Parkinson's disease to study the effects of H₂S on astrocytic activation in the mouse striatum, on the levels of tyrosine-hydroxylase (TH)-positive neuron loss, on the apomorphine-induced rotational behavior of the mice, and on the changes in ROCK2 and miR-135a-5p expression. Plasmid transfection was applied to modify miR-135a-5p levels in a neuronal cell line HCN-1A. Bioinformatics analysis was performed to predict the relationship between ROCK2 and miR-135a-5p in neuronal cells, and then was confirmed by luciferase reporter assay. Results: H₂S alleviated MPTP-induced astrocytic activation in the mouse striatum, alleviated the increases in TH-positive neuron loss, and improved the apomorphine-induced rotational behavior of the mice. H₂S significantly attenuated the increases in ROCK2 and the decreases in miR-135a-5p by MPTP. MiR-135a-5p targeted the 3'-UTR of ROCK2 mRNA to inhibit its translation in neuronal cells. Conclusion: MiR-135a-5p-regulated ROCK2 may play a role in the protective effects of hydrogen sulfide against Parkinson's disease.

show abstract

“…A number of further mutations have been associated with young‐onset Parkinson's disease including parkin PARK2 (Mori et al ., ; Farrer et al ., ; van de Warrenburg et al ., ; Pramstaller et al ., ) and PTEN‐induced putative kinase 1 PINK1 (Valente et al ., ; Lesage & Brice, ). These genes cause cellular dysfunction by generating misfolded proteins ( SNCA ; Siddiqui et al ., ), hyperactive kinases ( LRRK2 ; Luzón‐Toro et al ., ), dysfunctional ligases ( LRRK2 ; Klein & Westenberger, ) and involve mitochondrial oxidative stress ( DJ1; Lev et al ., ).…”

Section: Aetiology Of Parkinson's Diseasementioning

confidence: 99%

A neuroscience perspective of the gut theory of Parkinson's disease

Smith

Parr‐Brownlie

2018

Eur J of Neuroscience

View full text Add to dashboard Cite

Parkinson's disease is caused by complex interactions between environmental factors and a genetic predisposition. Environmental factors include exposure to pesticides and toxins, heavy metals and accumulation of iron and/or manganese in the brain. However, accumulating evidence indicates that gut-brain health and function are impaired in Parkinson's disease, often a decade before motor symptoms are diagnosed. We present the gut-brain theory of Parkinson's disease and summarise the peripheral and central nervous system pathology, gastrointestinal symptoms experienced by many Parkinson's patients, the route by which gut-brain dysfunction may occur and changes in gut microbiota that are associated with disease expression. Finally, we consider future gut-based treatments to prevent or slow down the progression of Parkinson's disease and explore whether this knowledge may highlight biomarkers to be included in complex algorithms in the future to assess a person's risk of developing Parkinson's disease.

show abstract

The Parkinson Disease gene SNCA: Evolutionary and structural insights with pathological implication

Cited by 143 publications

References 55 publications

Pharmacological targeting of α‐synuclein and TPPP/p25 in Parkinson's disease: challenges and opportunities in a Nutshell

Pharmacological targeting of α‐synuclein and TPPP/p25 in Parkinson's disease: challenges and opportunities in a Nutshell

Involvement of microRNA-135a-5p in the Protective Effects of Hydrogen Sulfide Against Parkinson's Disease

A neuroscience perspective of the gut theory of Parkinson's disease

Contact Info

Product

Resources

About