Advancing neurotrophic factors as treatments for age-related neurodegenerative diseases: developing and demonstrating “clinical proof-of-concept” for AAV-neurturin (CERE-120) in Parkinson's disease

2013 ◽  
Vol 34 (1) ◽  
pp. 35-61 ◽  
Author(s):  
Raymond T. Bartus ◽  
Tiffany L. Baumann ◽  
Lamar Brown ◽  
Brian R. Kruegel ◽  
Jeffrey M. Ostrove ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Neurodegenerative Diseases ◽  
Neurotrophic Factors ◽  
Proof Of Concept ◽  
Age Related

scholarly journals Pink1/Parkin link inflammation, mitochondrial stress, and neurodegeneration

2018 ◽  
Vol 217 (10) ◽  
pp. 3327-3329 ◽  
Author(s):  
Laura E. Newman ◽  
Gerald S. Shadel
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Mitochondrial Dna ◽  
Neurodegenerative Diseases ◽  
Mitochondrial Stress ◽  
Mitochondrial Dna Mutations ◽  
Dna Mutations ◽  
Age Related ◽  
Sting Pathway

What causes inflammation in age-related neurodegenerative diseases remains a mystery. Sliter et al. (2018. Nature. https://doi.org/10.1038/s41586-018-0448-9) show that, when damaged mitochondria cannot be removed by mitophagy, stress from exercise or mitochondrial DNA mutations activates the proinflammatory cGAS–STING pathway that may contribute to Parkinson’s disease.

scholarly journals Role of Mitochondria in Neurodegenerative Diseases: Mitochondria as a Therapeutic Target in Alzheimer's Disease

CNS Spectrums ◽  
2009 ◽  
Vol 14 (S7) ◽  
pp. 8-13 ◽  
Author(s):  
P. Hemachandra Reddy
Keyword(s):  
Alzheimer’S Disease ◽  
Parkinson’S Disease ◽  
Alzheimer's Disease ◽  
Parkinson's Disease ◽  
Cell Death ◽  
Neurodegenerative Diseases ◽  
Disease Progression ◽  
Neuronal Cell ◽  
Causal Factors ◽  
Age Related

A growing body of evidence suggests that mitochondrial abnormalities are involved in aging and in age-related neurodegenerative diseases as well as cancer, diabetes, and several other diseases known to be affected by mitochondria. Causal factors for most age-related neurodegenerative diseases—including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS), and Friedrich ataxia (FRDA)—are largely unknown. Genetic defects are reported to cause a small number of neurodegenerative diseases (Slide 1), but cellular, molecular, and pathological mechanisms of disease progression and selective neuronal cell death are not understood fully in these diseases. However, based on several cellular, molecular, and animal model studies of Alzheimer's disease, Parkinson's disease, ALS, FRDA, cancer, and diabetes, aging may play a large role in cell death in these diseases. Age-dependent, mitochondrially-generated reactive oxygen species (ROS) have been identified as important factors responsible for disease progression and cell death, particularly in late-onset diseases, in which genetic mutations are not causal factors.

scholarly journals Bidirectional Mendelian randomization analysis of shared genetic signals between coexisting neurodegenerative disorders to decipher underlying causal pathways

2019 ◽  
Author(s):  
Sandeep Grover ◽  
Keyword(s):  
Multiple Sclerosis ◽  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Neurodegenerative Diseases ◽  
Macular Degeneration ◽  
Neurodegenerative Disorders ◽  
Mendelian Randomization ◽  
Age Related Macular Degeneration ◽  
European Ancestry ◽  
Age Related

ABSTRACTOBJECTIVETo investigate whether coexistence of various neurodegenerative disorders is coincidental or biologically connected.DESIGNTwo sample Mendelian randomization using summary effect estimatesSETTINGGenetic data taken on various neurodegenerative disorders from various cohorts comprising individuals predominantly of European ancestry.PARTICIPANTSInternational Genomics of Alzheimer’s patients (IGAP), project MinE, International Age-related Macular Degeneration Consortium (IAMDGC), International Multiple Sclerosis Genetics Consortium (IMSGC), International Parkinson’s Disease Genomics Consortium (IPDGC)MAIN OUTCOME MEASURESAlzheimer’s disease (AD), Amyotrophic lateral sclerosis (ALS), Age related macular degeneration (AMD), Multiple sclerosis (MS) and Parkinson’s disease (PD).RESULTSA Bonferroni corrected threshold of P=0.005 was considered to be significant, and P<0.05 was considered suggestive of evidence for a potential association. I observed a risky effect of PD on ALS (OR = 1.126, 95% CI = 1.059-1.198, P = 0.005). Using AD as exposure and PD as outcome, I observed a risky effect of AD on PD using all the MR methods with strongest results using MBE method (OR = 2.072, 95% CI = 1.006-4.028, P = 0.0416). Genetic predisposition to AD was further observed to be a risky for AMD (OR = 1.759, 95% CI = 1.040-1.974, P = 0.0363). On the contrary, AMD was observed to be strongly protective towards MS (OR = 0.861, 95% CI = 0.776-0.955, P = 0.0059).CONCLUSIONSMy findings are consistent with the previously observed relative occurrence of co-existing neurodegenerative diseases or overlapping symptoms among neurodegenerative diseases.

scholarly journals Understanding the Multiple Role of Mitochondria in Parkinson’s Disease and Related Disorders: Lesson From Genetics and Protein–Interaction Network

2021 ◽  
Vol 9 ◽  
Author(s):  
Valentina Nicoletti ◽  
Giovanni Palermo ◽  
Eleonora Del Prete ◽  
Michelangelo Mancuso ◽  
Roberto Ceravolo
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Neurodegenerative Diseases ◽  
Mitochondrial Dysfunction ◽  
Disease Process ◽  
Interaction Network ◽  
Atp Production ◽  
Age Related ◽  
Process Understanding ◽  
Species Production

As neurons are highly energy-demanding cell, increasing evidence suggests that mitochondria play a large role in several age-related neurodegenerative diseases. Synaptic damage and mitochondrial dysfunction have been associated with early events in the pathogenesis of major neurodegenerative diseases, including Parkinson’s disease, atypical parkinsonisms, and Huntington disease. Disruption of mitochondrial structure and dynamic is linked to increased levels of reactive oxygen species production, abnormal intracellular calcium levels, and reduced mitochondrial ATP production. However, recent research has uncovered a much more complex involvement of mitochondria in such disorders than has previously been appreciated, and a remarkable number of genes and proteins that contribute to the neurodegeneration cascade interact with mitochondria or affect mitochondrial function. In this review, we aim to summarize and discuss the deep interconnections between mitochondrial dysfunction and basal ganglia disorders, with an emphasis into the molecular triggers to the disease process. Understanding the regulation of mitochondrial pathways may be beneficial in finding pharmacological or non-pharmacological interventions to delay the onset of neurodegenerative diseases.

scholarly journals Solriamfetol for Excessive Daytime Sleepiness in Parkinson's Disease: Phase 2 Proof‐of‐Concept Trial

2021 ◽  
Author(s):  
Aleksandar Videnovic ◽  
Amy W. Amara ◽  
Cynthia Comella ◽  
Paula K. Schweitzer ◽  
Helene Emsellem ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Excessive Daytime Sleepiness ◽  
Daytime Sleepiness ◽  
Phase 2 ◽  
Proof Of Concept

scholarly journals Hypoxia, Acidification and Inflammation: Partners in Crime in Parkinson’s Disease Pathogenesis?

Immuno ◽  
2021 ◽  
Vol 1 (2) ◽  
pp. 78-90
Author(s):  
Johannes Burtscher ◽  
Grégoire P. Millet
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Neurodegenerative Diseases ◽  
Current Knowledge ◽  
Cell Types ◽  
Brain Cell ◽  
Special Focus ◽  
Molecular Alterations ◽  
Research Fields

Like in other neurodegenerative diseases, protein aggregation, mitochondrial dysfunction, oxidative stress and neuroinflammation are hallmarks of Parkinson’s disease (PD). Differentiating characteristics of PD include the central role of α-synuclein in the aggregation pathology, a distinct vulnerability of the striato-nigral system with the related motor symptoms, as well as specific mitochondrial deficits. Which molecular alterations cause neurodegeneration and drive PD pathogenesis is poorly understood. Here, we summarize evidence of the involvement of three interdependent factors in PD and suggest that their interplay is likely a trigger and/or aggravator of PD-related neurodegeneration: hypoxia, acidification and inflammation. We aim to integrate the existing knowledge on the well-established role of inflammation and immunity, the emerging interest in the contribution of hypoxic insults and the rather neglected effects of brain acidification in PD pathogenesis. Their tight association as an important aspect of the disease merits detailed investigation. Consequences of related injuries are discussed in the context of aging and the interaction of different brain cell types, in particular with regard to potential consequences on the vulnerability of dopaminergic neurons in the substantia nigra. A special focus is put on the identification of current knowledge gaps and we emphasize the importance of related insights from other research fields, such as cancer research and immunometabolism, for neurodegeneration research. The highlighted interplay of hypoxia, acidification and inflammation is likely also of relevance for other neurodegenerative diseases, despite disease-specific biochemical and metabolic alterations.

scholarly journals The TOMM40 ‘523’ polymorphism in disease risk and age of symptom onset in two independent cohorts of Parkinson’s disease

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Megan C. Bakeberg ◽  
Madison E. Hoes ◽  
Anastazja M. Gorecki ◽  
Frances Theunissen ◽  
Abigail L. Pfaff ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Symptom Onset ◽  
Disease Risk ◽  
Age Of Onset ◽  
Sequencing Analysis ◽  
Age Related ◽  
Australian Cohort ◽  
Progression Markers ◽  
Age Related Cognitive Decline

AbstractAbnormal mitochondrial function is a key process in the pathogenesis of Parkinson’s disease (PD). The central pore-forming protein TOM40 of the mitochondria is encoded by the translocase of outer mitochondrial membrane 40 homologue gene (TOMM40). The highly variant ‘523’ poly-T repeat is associated with age-related cognitive decline and age of onset in Alzheimer’s disease, but whether it plays a role in modifying the risk or clinical course of PD it yet to be elucidated. The TOMM40 ‘523’ allele length was determined in 634 people with PD and 422 healthy controls from an Australian cohort and the Parkinson’s Progression Markers Initiative (PPMI) cohort, using polymerase chain reaction or whole genome sequencing analysis. Genotype and allele frequencies of TOMM40 ‘523’ and APOE ε did not differ significantly between the cohorts. Analyses revealed TOMM40 ‘523’ allele groups were not associated with disease risk, while considering APOE ε genotype. Regression analyses revealed the TOMM40 S/S genotype was associated with a significantly later age of symptom onset in the PPMI PD cohort, but not after correction for covariates, or in the Australian cohort. Whilst variation in the TOMM40 ‘523’ polymorphism was not associated with PD risk, the possibility that it may be a modifying factor for age of symptom onset warrants further investigation in other PD populations.

scholarly journals Protein Binding Partners of Dysregulated miRNAs in Parkinson’s Disease Serum

Cells ◽  
2021 ◽  
Vol 10 (4) ◽  
pp. 791
Author(s):  
Wolfgang P. Ruf ◽  
Axel Freischmidt ◽  
Veselin Grozdanov ◽  
Valerie Roth ◽  
Sarah J. Brockmann ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Protein Binding ◽  
Neurodegenerative Diseases ◽  
Extracellular Vesicles ◽  
Abundance Pattern ◽  
Binding Partners ◽  
Direct Binding ◽  
Unsupervised Approach ◽  
High Degree

Accumulating evidence suggests that microRNAs (miRNAs) are a contributing factor to neurodegenerative diseases. Although altered miRNA profiles in serum or plasma have been reported for several neurodegenerative diseases, little is known about the interaction between dysregulated miRNAs and their protein binding partners. We found significant alterations of the miRNA abundance pattern in serum and in isolated serum-derived extracellular vesicles of Parkinson’s disease (PD) patients. The differential expression of miRNA in PD patients was more robust in serum than in isolated extracellular vesicles and could separate PD patients from healthy controls in an unsupervised approach to a high degree. We identified a novel protein interaction partner for the strongly dysregulated hsa-mir-4745-5p. Our study provides further evidence for the involvement of miRNAs and HNF4a in PD. The demonstration that miRNA-protein binding might mediate the pathologic effects of HNF4a both by direct binding to it and by binding to proteins regulated by it suggests a complex role for miRNAs in pathology beyond the dysregulation of transcription.

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