Juvenile-Onset Parkinsonism as a Result of the First Mutation in the Adenosine Triphosphate Orientation Domain of PINK1

Leutenegger, Anne-Louise; Salih, Mustafa A.; Ibáñez, Pablo; Mukhtar, Maowia M.; Lesage, Suzanne; Arabi, Ali; Lohmann, Ebba; Dürr, Alexandra; Ahmed, Ammar; Brice, Alexis

doi:10.1001/archneur.63.9.1257

Cited by 40 publications

(35 citation statements)

References 9 publications

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“…PARK6 (gene PINK1, PTEN-induced putative kinase 1): It is characterized by early onset in most patients (mean age at onset in the 30s, ranging from childhood until the seventh decade of life), dystonia at onset or symptom symmetry in some cases, slow disease progression, excellent levodopa responsiveness, early peak-dose dyskinesias; hyperreflexia has been described; rare cases with very early onset display sleep benefit and diurnal fluctuations (Valente et al 2001(Valente et al , 2002Bonifati 2005;Ibáñez et al 2006;Leutenegger et al 2006). Psychiatric disturbances such as depression, anxiety, and psychosis are a frequent finding (Bonifati 2005;Ibáñez et al 2006;Steinlechner et al 2007).…”

Section: Clinical Approach To Parkinson's Diseasementioning

confidence: 99%

Clinical Approach to Parkinson's Disease: Features, Diagnosis, and Principles of Management

Massano

Bhatia

2012

Cold Spring Harbor Perspectives in Medicine

333

222

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Section: Clinical Approach To Parkinson's Diseasementioning

confidence: 99%

Clinical Approach to Parkinson's Disease: Features, Diagnosis, and Principles of Management

Massano

Bhatia

2012

Cold Spring Harbor Perspectives in Medicine

333

222

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“…The majority of PD cases are sporadic and of unknown origin, but several genes have been identified that, when mutated, give rise to the rare, familial forms of the disease. It may therefore be argued that there are more than just 2 types, while further studies have indicated that the genetic basis may, however, be even more complex [109][110][111]. Thus, as with GTS, the many phenotypes and aetiologies (both genetic and nongenetic) of PD are more complex than was once thought.…”

Section: Aetiological Theories In Gts and The Possible Effect On Prevmentioning

confidence: 99%

The prevalence and epidemiology of Gilles de la Tourette syndrome

Robertson

2008

Journal of Psychosomatic Research

177

108

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“…PINK1 families exhibit an earlier onset of disease (range of 9-52 years), accompanied by sustained responses to levodopa treatment (9,57,64,103). Autopsy findings have been reported from one family, showing classic Lewy body pathology (92).…”

Section: Introductionmentioning

confidence: 99%

Beyond Mitophagy: Cytosolic PINK1 as a Messenger of Mitochondrial Health

Steer

Dail

Chu

2015

Antioxidants & Redox Signaling

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Significance: Disruptions in mitochondrial homeostasis are implicated in human diseases across the lifespan. Recessive mutations in PINK1, which encodes the mitochondrially targeted PTEN-induced putative kinase 1 (PINK1), cause an autosomal recessive form of Parkinson's disease. As with all kinases, PINK1 participates in multiple functional pathways, and its dysregulation has been implicated in a growing number of diseases. Recent Advances: In addition to its heavily studied role in mitophagy, PINK1 regulates mitochondrial respiratory function, reactive oxygen species generation, and mitochondrial transport. Moreover, recent studies implicate processed PINK1 in cytosolic signaling cascades that promote cell survival and neuron differentiation. Cytosolic PINK1 is also capable of suppressing autophagy and mitophagy. We propose a working hypothesis that PINK1 is released by functional mitochondria as a signal to coordinate cell growth and differentiation in response to mitochondrial status. Critical Issues: PINK1 biology needs to be better understood in primary neurons, as the stability and subcellular localization of PINK1 is differentially regulated in different cell types. Delineating factors that regulate its mitochondrial import/export, processing by different peptidases, kinase activity, subcellular localization, and degradation will be important for defining relevant downstream kinase targets. Future Directions: It is becoming clear that different subcellular pools of PINK1 mediate distinct functions. Future studies will undoubtedly expand on the spectrum of cellular functions regulated by PINK1. Continued study of cytosolic PINK1 may offer novel insights into how functional mitochondria communicate their status with the rest of the cell. Antioxid. Redox Signal. 22, 1047-1059. P arkinson's disease (PD) is a debilitating age-related neurodegenerative disorder that affects 4-5 million people in the world's most populous nations (28). PD pathology is characterized by: (i) Lewy body inclusions, which contain alpha-synuclein and ubiquitin, in autonomic, brainstem and cortical regions (10), and (ii) the loss of pigmented brain stem neurons from the substantia nigra and locus ceruleus. Degeneration of dopaminergic nigral neurons account for the classic motor signs, although other neuron groups are also affected. While the majority of PD cases are idiopathic, studies of gene products implicated in familial PD implicate common pathways that are likely to be important for disease progression (101).Mutations in PINK1, which encodes PTEN-induced putative kinase 1 (PINK1), represent the second most common cause of autosomal recessive parkinsonism (48,103). PINK1 families exhibit an earlier onset of disease (range of 9-52 years), accompanied by sustained responses to levodopa treatment (9,57,64,103). Autopsy findings have been reported from one family, showing classic Lewy body pathology (92). Pathways regulated by PINK1 appear to interact with other PD-linked genes (11,20,91), and PINK1 enhances the resistance of...

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Juvenile-Onset Parkinsonism as a Result of the First Mutation in the Adenosine Triphosphate Orientation Domain of PINK1

Cited by 40 publications

References 9 publications

Clinical Approach to Parkinson's Disease: Features, Diagnosis, and Principles of Management

Clinical Approach to Parkinson's Disease: Features, Diagnosis, and Principles of Management

The prevalence and epidemiology of Gilles de la Tourette syndrome

Beyond Mitophagy: Cytosolic PINK1 as a Messenger of Mitochondrial Health

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