Miro1 Marks Parkinson’s Disease Subset and Miro1 Reducer Rescues Neuron Loss in Parkinson’s Models

Hsieh, Chung Han; Li, Li; Vanhauwaert, Roeland; Nguyen, Kong T.; Davis, Mary Dabney; Bu, Guojun; Wszołek, Zbigniew K.; Wang, Xinnan

doi:10.1016/j.cmet.2019.08.023

Cited by 113 publications

(169 citation statements)

References 36 publications

Supporting

Mentioning

154

Contrasting

Order By: Relevance

“…In Parkinson's disease patient‐derived neurons, impairment of flux through this pathway resulted in decreased mitochondrial clearance via mitophagy. Indeed, there are increased levels of mitochondria in addition to higher levels of Miro expression . Based on these observations, an in silico small molecule inhibitor of Miro was developed with the goal of reducing Miro levels in order to promote mitophagy .…”

Section: Miro Regulation In Neurodegenerative Diseasementioning

confidence: 99%

“…Indeed, there are increased levels of mitochondria in addition to higher levels of Miro expression . Based on these observations, an in silico small molecule inhibitor of Miro was developed with the goal of reducing Miro levels in order to promote mitophagy . Promisingly, “Miro reducer” decreased Miro expression levels in Parkinson's disease neurons and increased mitophagy, potentially opening the door to future therapeutic strategies to promote the clearance of damaged mitochondria from Parkinson's disease patients.…”

Section: Miro Regulation In Neurodegenerative Diseasementioning

confidence: 99%

See 1 more Smart Citation

Miro: A molecular switch at the center of mitochondrial regulation

et al. 2020

View full text Add to dashboard Cite

The orchestration of mitochondria within the cell represents a critical aspect of cell biology. At the center of this process is the outer mitochondrial membrane protein, Miro. Miro coordinates diverse cellular processes by regulating connections between organelles and the cytoskeleton that range from mediating contacts between the endoplasmic reticulum and mitochondria to the regulation of both actin and microtubule motor proteins. Recently, a number of cell biological, biochemical, and protein structure studies have helped to characterize the myriad roles played by Miro. In addition to answering questions regarding Miro's function, these studies have opened the door to new avenues in the study of Miro in the cell. This review will focus on summarizing recent findings for Miro's structure, function, and activity while highlighting key questions that remain unanswered.

show abstract

Section: Miro Regulation In Neurodegenerative Diseasementioning

confidence: 99%

Section: Miro Regulation In Neurodegenerative Diseasementioning

confidence: 99%

Miro: A molecular switch at the center of mitochondrial regulation

et al. 2020

View full text Add to dashboard Cite

show abstract

“…First, the failure to remove Miro1 from damaged mitochondria clearly exists in nonneuronal cells. We have established sensitive assays to measure Miro1 response to mitochondrial depolarization in skin fibroblasts from a total of 83 PD patients and discovered that 94% of them show impairment in removing Miro1 from damaged mitochondria 31 . The convenience of acquiring skin cells from PD patients by a simple biopsy opens the door to novel biomarker research on Miro1.…”

Section: Miro1 Protein: a Linchpin For Mitochondrial Motility And Quamentioning

confidence: 99%

Precision Neurology for Parkinson’s Disease: Coupling Miro1‐Based Diagnosis With Drug Discovery

Bharat

Wang

2020

Movement Disorders

Self Cite

View full text Add to dashboard Cite

Parkinson’s disease (PD) is a debilitating movement disorder, significantly afflicting the aging population. Efforts to develop an effective treatment have been challenged by the lack of understanding of the pathological mechanisms underlying neurodegeneration. We have shown that Miro1, an outer mitochondrial membrane protein, situates at the intersection of the complex genetic and functional network of PD. Removing Miro1 from the surface of damaged mitochondria is a prerequisite for mitochondrial clearance via mitophagy. Parkinson’s proteins PINK1, Parkin, and LRRK2 are the molecular helpers to remove Miro1 from dysfunctional mitochondria destined for mitophagy. We have found a delay in clearing Miro1 and initiating mitophagy in postmortem brains and induced pluripotent stem cell–derived neurons from PD patients harboring mutations in LRRK2, PINK1, or Parkin, or from sporadic PD patients with no known mutations. In addition, we have shown that reducing Miro1 by both genetic and pharmacological approaches can correct this Miro1 phenotype and rescue Parkinson’s‐relevant phenotypes in human neurons and fly PD models. These results suggest that the Miro1 defect may be a common denominator for PD, and compounds that reduce Miro1 promise a new class of drugs to battle PD. We propose to couple this Miro1 phenotype with Miro1‐based drug discovery in future therapeutic studies, which could significantly improve the success of clinical trials. © 2020 International Parkinson and Movement Disorder Society

show abstract

“…These findings indicate that Miro may be a converging therapeutic target in genetically distinct ALS/FTD patients. Importantly, we have previously shown that small molecules removing Miro from damaged mitochondria rescue neuron loss and improve locomotor abilities in Parkinson's disease models (Hsieh et al, 2019). Therefore, pharmacologically manipulating Miro seems to have great potential for treating multiple neurodegenerative diseases.…”

Section: Discussionmentioning

confidence: 99%

Drosophila VCP/p97 Mediates Dynein-Dependent Retrograde Mitochondrial Motility in Axons

Gonzalez

Wang

2020

Front. Cell Dev. Biol.

Self Cite

View full text Add to dashboard Cite

Valosin-containing protein (VCP), also called p97, is an evolutionarily conserved and ubiquitously expressed ATPase with diverse cellular functions. Dominant mutations in VCP are found in a late-onset multisystem degenerative proteinopathy. The neurological manifestations of the disorder include frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). In these patients, long motor neuron axons could be particularly susceptible to defects in axonal transport. However, whether VCP has a physiological function in maintaining axonal transport and whether this role is impaired by disease-causing mutations remains elusive. Here, by employing live-imaging methods in Drosophila larval axons and performing genetic interaction experiments, we discover that VCP regulates the axonal transport of mitochondria. Downregulation of VCP enhances the retrograde transport of mitochondria and reduces the density of mitochondria in larval axons. This unidirectional motility phenotype is rescued by removing one copy of the retrograde motor dynein heavy chain (DHC), or elevating Miro which facilitates anterograde mitochondrial movement by interacting with the anterograde motor kinesin heavy chain (KHC). Importantly, Miro upregulation also significantly improves ATP production of VCP mutant larvae. We investigate human VCP pathogenic mutations in our fly system. We find that expressing these mutations affects mitochondrial transport in the same way as knocking down VCP. Our results reveal a new role of VCP in mediating axonal mitochondrial transport, and provide evidence implicating impaired mitochondrial motility in the pathophysiology of VCP-relevant neurodegenerative diseases.

show abstract

Miro1 Marks Parkinson’s Disease Subset and Miro1 Reducer Rescues Neuron Loss in Parkinson’s Models

Cited by 113 publications

References 36 publications

Miro: A molecular switch at the center of mitochondrial regulation

Miro: A molecular switch at the center of mitochondrial regulation

Precision Neurology for Parkinson’s Disease: Coupling Miro1‐Based Diagnosis With Drug Discovery

Drosophila VCP/p97 Mediates Dynein-Dependent Retrograde Mitochondrial Motility in Axons

Contact Info

Product

Resources

About