Journal ArticleDOI
Admixing of MPTP-Resistant and Susceptible Mice Strains Augments Nigrostriatal Neuronal Correlates to Resist MPTP-Induced Neurodegeneration
TLDR
The core neuroanatomical features of resilience against PD and evidence for ethnicity-based differential prevalence are presented and similar neural correlates of resilience are envisaged in the Anglo-Indian population.Abstract:
Disease genetics in admixed populations like Hispanic-Americans, African-Americans, etc. are gaining importance due to high disease burden in them. Furthermore, epidemiological studies conclusively prove ethnicity-based differential prevalence of Parkinson's disease (PD), since the American-Caucasians are more susceptible than Asian-Indians and Africans. Contradictorily, Anglo-Indians, an admixture of Europeans and Asian-Indians are five-times less susceptible than Indians. We evaluated the neural basis of this phenomenon using the cytomorphological features of susceptibility to nigrostriatal neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). The nigral dopaminergic neuronal numbers, their size and tyrosine hydroxylase (TH), PitX3 and Nurr1 expression were compared in MPTP-susceptible C57BL/6J mice, MPTP-resistant CD-1 mice and their crossbreds using stereology, morphometry and densitometry. Apoptotic index was evaluated by TUNEL-assay and caspase-3 expression. Striatal volume, TH and glial derived neurotrophic factor (GDNF) expression were studied. The normal CD-1 and crossbreds had significantly more, although smaller, nigral dopaminergic neurons than C57BL/6J, and a larger striatum. The crossbreds had higher TH, Nurr1 and PitX3 levels. MPTP administration caused loss of ~50-60 % nigral dopaminergic neurons in C57BL/6J and ~15 % in CD-1, but none in crossbreds. MPTP-induced cellular shrinkage in C57BL/6J was contrasted by nuclear enlargement without somal alterations in resistant strains. MPTP lowered the striatal TH and GDNF in C57BL/6J. Elevated striatal GDNF in CD-1 and crossbreds could be of compensatory nature and complemented the reduced nigral caspase-3 expression to attenuate and/or block apoptosis. Similar neural correlates of resilience are envisaged in the Anglo-Indian population. Thus, we present the core neuroanatomical features of resilience against PD and evidence for ethnicity-based differential prevalence.read more
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Journal ArticleDOI
Role of the endolysosomal system in Parkinson's disease.
TL;DR: Interestingly, α‐synuclein and LRRK2, key proteins involved in PD, function in different steps of the E‐L pathway and target their components to induce disease pathogenesis.
Journal ArticleDOI
A novel autophagy modulator 6-Bio ameliorates SNCA/α-synuclein toxicity.
Sumathi Suresh,Aravinda K Chavalmane,Vidyadhara Dj,Haorei Yarreiphang,Shashank Rai,Abhik Paul,James P. Clement,Phalguni Anand Alladi,Ravi Manjithaya +8 more
TL;DR: Importantly, neuroprotective function of 6-Bio as envisaged by immunohistology and behavior analyses in a preclinical model of PD where it induces autophagy in dopaminergic neurons of mice midbrain to clear toxic protein aggregates suggesting that it could be a potential therapeutic candidate for protein conformational disorders.
Journal ArticleDOI
Modulation of Autophagy by a Small Molecule Inverse Agonist of ERRα Is Neuroprotective.
Sumathi Suresh,Aravinda K Chavalmane,Malini S. Pillai,Veena Ammanathan,D.J. Vidyadhara,Haorei Yarreiphang,Shashank Rai,Abhik Paul,James P. Clement,Phalguni Anand Alladi,Ravi Manjithaya +10 more
TL;DR: The role of Estrogen Related Receptor α (ERRα, HUGO Gene Nomenclature ESRRA), new molecular player of aggrephagy, in keeping autophagy flux in check by inhibiting autophagosome formation is reported and described.
Journal ArticleDOI
Small molecule modulator of aggrephagy regulates neuroinflammation to curb pathogenesis of neurodegeneration
Sumathi Suresh,Sumathi Suresh,Janhavi Pandurangi,Ravi Kumar Murumalla,D.J. Vidyadhara,D.J. Vidyadhara,Lakshmi Garimella,Achyuth Acharya,Shashank Rai,Shashank Rai,Abhik Paul,Haorei Yarreiphang,Malini S. Pillai,Mridhula Giridharan,James P. Clement,Phalguni Anand Alladi,Taslimarif Saiyed,Ravi Manjithaya +17 more
TL;DR: In vivo studies show that PD180970 is neuroprotective by degrading the toxic protein oligomers through induction of autophagy and subsiding the microglial activation, and these protective mechanisms ensure the negation of Parkinson's disease related motor impairments.
Journal ArticleDOI
NR4A2 genetic variation and Parkinson's disease: Evidence from a systematic review and meta-analysis.
Hongmei Liu,Hongbo Liu,Ting Li,Jiayi Cui,Yingmei Fu,Juanjuan Ren,Xiujia Sun,Ping Jiang,Shunying Yu,Chunbo Li +9 more
TL;DR: The study comprehensively evaluated the association of NR4A2 variation with PD, and the results failed to demonstrate that the NR3A2 polymorphisms significantly associated with PD except for rs35479735, suggesting that more studies are needed to elucidate if NR4 a2 is a risk of PD.
References
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Book
The Mouse Brain in Stereotaxic Coordinates
TL;DR: The 3rd edition of this atlas is now in more practical 14"x11" format for convenient lab use and includes a CD of all plates and diagrams, as well as Adobe Illustrator files of the diagrams, and a variety of additional useful material.
Journal ArticleDOI
GDNF: a glial cell line-derived neurotrophic factor for midbrain dopaminergic neurons
TL;DR: In embryonic midbrain cultures, recombinant human GDNF promoted the survival and morphological differentiation of dopaminergic neurons and increased their high-affinity dopamine uptake and did not increase total neuron or astrocyte numbers or transmitter uptake.
Journal ArticleDOI
Genome-wide association study reveals genetic risk underlying Parkinson's disease
Javier Simón-Sánchez,Claudia Schulte,Jose Bras,Jose Bras,Manu Sharma,J. Raphael Gibbs,J. Raphael Gibbs,Daniela Berg,Coro Paisán-Ruiz,Peter Lichtner,Sonja W. Scholz,Sonja W. Scholz,Dena G. Hernandez,Dena G. Hernandez,Rejko Krüger,Monica Federoff,Christine Klein,Alison Goate,Joel S. Perlmutter,Michael Bonin,Mike A. Nalls,Thomas Illig,Christian Gieger,Henry Houlden,Michael Steffens,Michael S. Okun,Brad A. Racette,Mark R. Cookson,Kelly D. Foote,Hubert H. Fernandez,Bryan J. Traynor,Stefan Schreiber,Sampath Arepalli,Ryan R. Zonozi,Katrina Gwinn,Marcel P. van der Brug,Marcel P. van der Brug,Grisel Lopez,Stephen J. Chanock,Arthur Schatzkin,Yikyung Park,Albert R. Hollenbeck,Jianjun Gao,Xuemei Huang,Nicholas W. Wood,Delia Lorenz,Günther Deuschl,Honglei Chen,Olaf Riess,John Hardy,Andrew B. Singleton,Thomas Gasser +51 more
TL;DR: It is demonstrated that an unequivocal role for common genetic variants in the etiology of typical PD and population-specific genetic heterogeneity in this disease is suggested, and supporting evidence that common variation around LRRK2 modulates risk for PD is provided.
Journal ArticleDOI
Neurodegeneration prevented by lentiviral vector delivery of GDNF in primate models of Parkinson's disease.
Jeffrey H. Kordower,Marina E. Emborg,Jocelyne Bloch,Shuang Y. Ma,Yaping Chu,Liza Leventhal,Jodi L. McBride,Er-Yun Chen,Stéphane Palfi,Ben Roitberg,W. Douglas Brown,James E. Holden,Robert W. Pyzalski,Michael D. Taylor,Paul M. Carvey,Zaodung Ling,Didier Trono,Philippe Hantraye,Nicole Déglon,Patrick Aebischer,Patrick Aebischer +20 more
TL;DR: Data indicate that GDNF delivery using a lentiviral vector system can prevent nigrostriatal degeneration and induce regeneration in primate models of PD and might be a viable therapeutic strategy for PD patients.