scholarly journals Role of Cleaved PINK1 in Neuronal Development, Synaptogenesis, and Plasticity: Implications for Parkinson’s Disease

2021 ◽  
Vol 15 ◽  
Author(s):  
Smijin K. Soman ◽  
Ruben K. Dagda
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Neuronal Development ◽  
Structural Integrity ◽  
Intermembrane Space ◽  
Loss Of Function ◽  
Serine Threonine Kinase ◽  
Functional Roles ◽  
Neuronal Functions

Mitochondrial dysfunction plays a significant role in the pathogenesis of Parkinson’s disease (PD). Consistent with this concept, loss of function mutations in the serine/threonine kinase- PINK1 (PTEN-induced putative kinase-1) causes autosomal recessive early onset PD. While the functional role of f-PINK1 (full-length PINK1) in clearing dysfunctional mitochondria via mitophagy is extensively documented, our understanding of specific physiological roles that the non-mitochondrial pool of PINK1 imparts in neurons is more limited. PINK1 is proteolytically processed in the intermembrane space and matrix of the mitochondria into functional cleaved products (c-PINK1) that are exported to the cytosol. While it is clear that posttranslational processing of PINK1 depends on the mitochondria’s oxidative state and structural integrity, the functional roles of c-PINK1 in modulating neuronal functions are poorly understood. Here, we review the diverse roles played by c-PINK1 in modulating various neuronal functions. Specifically, we describe the non-canonical functional roles of PINK1, including but not limited to: governing mitochondrial movement, neuronal development, neuronal survival, and neurogenesis. We have published that c-PINK1 stimulates neuronal plasticity and differentiation via the PINK1-PKA-BDNF signaling cascade. In addition, we provide insight into how mitochondrial membrane potential-dependent processing of PINK1 confers conditional retrograde signaling functions to PINK1. Further studies delineating the role of c-PINK1 in neurons would increase our understanding regarding the role played by PINK1 in PD pathogenesis.

scholarly journals Parkin is recruited selectively to impaired mitochondria and promotes their autophagy

2008 ◽  
Vol 183 (5) ◽  
pp. 795-803 ◽  
Author(s):  
Derek Narendra ◽  
Atsushi Tanaka ◽  
Der-Fen Suen ◽  
Richard J. Youle
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Mammalian Cells ◽  
Loss Of Function ◽  
Gene Coding ◽  
Selective Elimination ◽  
Mitochondrial Toxins ◽  
Early Onset Parkinson’S Disease ◽  
Increased Susceptibility

Loss-of-function mutations in Park2, the gene coding for the ubiquitin ligase Parkin, are a significant cause of early onset Parkinson's disease. Although the role of Parkin in neuron maintenance is unknown, recent work has linked Parkin to the regulation of mitochondria. Its loss is associated with swollen mitochondria and muscle degeneration in Drosophila melanogaster, as well as mitochondrial dysfunction and increased susceptibility to mitochondrial toxins in other species. Here, we show that Parkin is selectively recruited to dysfunctional mitochondria with low membrane potential in mammalian cells. After recruitment, Parkin mediates the engulfment of mitochondria by autophagosomes and the selective elimination of impaired mitochondria. These results show that Parkin promotes autophagy of damaged mitochondria and implicate a failure to eliminate dysfunctional mitochondria in the pathogenesis of Parkinson's disease.

Movement without dopamine: striatal dopamine is required to maintain but not to perform learned actions

2007 ◽  
Vol 35 (2) ◽  
pp. 428-432 ◽  
Author(s):  
E. Dowd ◽  
S.B. Dunnett
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Motor Learning ◽  
Motor Performance ◽  
Striatal Dopamine ◽  
Motor Deficits ◽  
Functional Roles ◽  
Gene Therapies ◽  
Different Populations

The different populations of dopaminergic neurons located in the ventral mesencephalon have long been associated with distinct functional roles. The nigrostriatal projection is considered necessary for efficient motor performance, while the mesolimbocortical projection is usually associated with reward signalling. However, a number of recent studies in our laboratory suggest that the divergence between these two functions of dopamine is not as delineated as it may once have seemed. In these experiments, we have been developing improved behavioural methods for assessing the nature of the deficit in rats with unilateral dopamine lesions, as well as the efficacy of various experimental cell and gene therapies for Parkinson's disease. The behavioural task we selected is a lateralized nose-poking task in which rats are trained to respond to stimulus lights on either side of their heads. This task not only allows us to accurately measure aspects of motor performance, but, because it requires extensive training, it also allows us to assess aspects of motor learning. The concurrence of motor performance parameters (which are considered to be dependent on striatal dopamine) and motor learning parameters (which are thought to be dependent on mesolimbocortical reward signalling) within the same task has revealed some surprising consequences of dopamine lesions and neuroprotective/neuroreparative approaches to repair in rat models of Parkinson's disease. The data generated using this task suggest that the motor deficits that occur as a consequence of dopamine lesions may be downstream of a deficit in reward signalling. If so, this could redefine our perception of the role of dopamine in controlling motor function.

scholarly journals Loss of UCHL1 rescues the defects related to Parkinson’s disease by suppressing glycolysis

2021 ◽  
Vol 7 (28) ◽  
pp. eabg4574
Author(s):  
Su Jin Ham ◽  
Daewon Lee ◽  
Wen Jun Xu ◽  
Eunjoo Cho ◽  
Sekyu Choi ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Protein Kinase ◽  
Pyruvate Kinase ◽  
Mammalian Cells ◽  
Loss Of Function ◽  
Tripartite Motif ◽  
Carboxyl Terminal ◽  
Amp Activated Protein Kinase

The role of ubiquitin carboxyl-terminal hydrolase L1 (UCHL1; also called PARK5) in the pathogenesis of Parkinson’s disease (PD) has been controversial. Here, we find that the loss of UCHL1 destabilizes pyruvate kinase (PKM) and mitigates the PD-related phenotypes induced by PTEN-induced kinase 1 (PINK1) or Parkin loss-of-function mutations in Drosophila and mammalian cells. In UCHL1 knockout cells, cellular pyruvate production and ATP levels are diminished, and the activity of AMP–activated protein kinase (AMPK) is highly induced. Consequently, the activated AMPK promotes the mitophagy mediated by Unc-51–like kinase 1 (ULK1) and FUN14 domain–containing 1 (FUNDC1), which underlies the effects of UCHL1 deficiency in rescuing PD-related defects. Furthermore, we identify tripartite motif–containing 63 (TRIM63) as a previously unknown E3 ligase of PKM and demonstrate its antagonistic interaction with UCHL1 to regulate PD-related pathologies. These results suggest that UCHL1 is an integrative factor for connecting glycolysis and PD pathology.

scholarly journals Therapeutic Potential of Vital Transcription Factors in Alzheimer’s and Parkinson’s Disease With Particular Emphasis on Transcription Factor EB Mediated Autophagy

2021 ◽  
Vol 15 ◽  
Author(s):  
Sachchida Nand Rai ◽  
Neeraj Tiwari ◽  
Payal Singh ◽  
Divya Mishra ◽  
Anurag Kumar Singh ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Transcription Factor ◽  
Neurodegenerative Disorders ◽  
Structural Integrity ◽  
Therapeutic Potential ◽  
Transcription Factor Eb ◽  
Autophagy Pathway ◽  
Common Observation

Autophagy is an important cellular self-digestion and recycling pathway that helps in maintaining cellular homeostasis. Dysregulation at various steps of the autophagic and endolysosomal pathway has been reported in several neurodegenerative disorders such as Alzheimer’s disease (AD), Parkinson’s disease (PD), and Huntington disease (HD) and is cited as a critically important feature for central nervous system (CNS) proteostasis. Recently, another molecular target, namely transcription factor EB (TFEB) has been explored globally to treat neurodegenerative disorders. This TFEB, is a key regulator of autophagy and lysosomal biogenesis pathway. Multiple research studies suggested therapeutic potential by targeting TFEB to treat human diseases involving autophagy-lysosomal dysfunction, especially neurodegenerative disorders. A common observation involving all neurodegenerative disorders is their poor efficacy in clearing and recycle toxic aggregated proteins and damaged cellular organelles due to impairment in the autophagy pathway. This dysfunction in autophagy characterized by the accumulation of toxic protein aggregates leads to a progressive loss in structural integrity/functionality of neurons and may even result in neuronal death. In recent years TFEB, a key regulator of autophagy and lysosomal biogenesis, has received considerable attention. It has emerged as a potential therapeutic target in numerous neurodegenerative disorders like AD and PD. In various neurobiology studies involving animal models, TFEB has been found to ameliorate neurotoxicity and rescue neurodegeneration. Since TFEB is a master transcriptional regulator of autophagy and lysosomal biogenesis pathway and plays a crucial role in defining autophagy activation. Studies have been done to understand the mechanisms for TFEB dysfunction, which may yield insights into how TFEB might be targeted and used for the therapeutic strategy to develop a treatment process with extensive application to neurodegenerative disorders. In this review, we explore the role of different transcription factor-based targeted therapy by some natural compounds for AD and PD with special emphasis on TFEB.

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