Are Parkinson disease patients protected from some but not all cancers?

Inzelberg, Rivka; Jankovic, Joseph

doi:10.1212/01.wnl.0000277638.63767.b8

Cited by 115 publications

(117 citation statements)

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“…In this way, the BH4 domain of Bcl-xL is maintained and the full-length protein can exert its anti-apoptotic function p-Bcl-xL by PINK1 protects from CCCP-induced death G Arena et al suggesting that common genes and pathways might be implicated in both diseases. 38 PINK1 was identified for the first time through a gene expression screening in ovarian carcinoma cells overexpressing PTEN, a key tumor suppressor gene, which is mutated in several malignancies. 39 Recent data have proposed a novel function of PINK1 in promoting carcinogenesis, insofar PINK1 silencing was shown to downregulate Bcl-xL expression in bladder cancer cells, sensitizing them to ROS-mediated cell death.…”

Section: Discussionmentioning

confidence: 99%

PINK1 protects against cell death induced by mitochondrial depolarization, by phosphorylating Bcl-xL and impairing its pro-apoptotic cleavage

et al. 2013

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Mutations in the PINK1 gene are a frequent cause of autosomal recessive Parkinson's disease (PD). PINK1 encodes a mitochondrial kinase with neuroprotective activity, implicated in maintaining mitochondrial homeostasis and function. In concurrence with Parkin, PINK1 regulates mitochondrial trafficking and degradation of damaged mitochondria through mitophagy. Moreover, PINK1 can activate autophagy by interacting with the pro-autophagic protein Beclin-1. Here, we report that, upon mitochondrial depolarization, PINK1 interacts with and phosphorylates Bcl-xL, an anti-apoptotic protein also known to inhibit autophagy through its binding to Beclin-1. PINK1-Bcl-xL interaction does not interfere either with Beclin-1 release from Bcl-xL or the mitophagy pathway; rather it protects against cell death by hindering the pro-apoptotic cleavage of Bcl-xL. Our data provide a functional link between PINK1, Bcl-xL and apoptosis, suggesting a novel mechanism through which PINK1 regulates cell survival. This pathway could be relevant for the pathogenesis of PD as well as other diseases including cancer. Parkinson's disease (PD) is the second most common neurodegenerative disorder after Alzheimer's disease, with prevalence of 1% in the population older than 60 years. 1 Several biochemical abnormalities, including mitochondrial dysfunction, oxidative stress and misfolded protein damage, have been implicated in PD pathogenesis. 2 Although the majority of late-onset cases are sporadic, early-onset PD is frequently caused by mutations in genes with autosomal recessive inheritance, mainly Parkin (GeneID: 5071) and PINK1 (GeneID: 65018). 3 PINK1 encodes a 63 kDa mitochondrial protein kinase, which is processed by mitochondrial proteases to generate two smaller isoforms. [4][5][6][7] We and others have shown that PINK1 acts as a key neuroprotective protein, aimed at preventing mitochondrial dysfunction and apoptotic cell death in response to multiple stress conditions. [8][9][10] This pro-survival activity is exerted through several mechanisms, including phosphorylation of the mitochondrial proteins TRAP1 and Omi/HtrA2, and regulation of mitochondrial calcium buffering. [11][12][13][14] Increasing data now indicate that PINK1 acts upstream of Parkin in an evolutionary conserved pathway implicated in regulating mitochondrial biogenesis, trafficking and fusion/ fission events, to maintain mitochondrial network health. 15 In particular, upon mitochondrial depolarization, PINK1 processing is impaired, determining a marked accumulation of the full-length protein on the surface of dysfunctional mitochondria, where it recruits Parkin. This process results in the phosphorylation and/or ubiquitination of several mitochondrial substrates, leading to the selective quarantine of damaged mitochondria and their degradation through mitophagy. [16][17][18][19] In line with this, we reported that coexpression of mutant, but not wild-type (wt) PINK1, with mutant alpha-synuclein resulted in the formation of enlarged autophagosomes surrounding abnormal mitoch...

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Section: Discussionmentioning

confidence: 99%

PINK1 protects against cell death induced by mitochondrial depolarization, by phosphorylating Bcl-xL and impairing its pro-apoptotic cleavage

et al. 2013

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“…Still, considering more recent studies, in particular cohort studies, evidence for a lower cancer risk among PD patients is fairly consistent. Underlying mechanisms are unclear, although several authors suggested shared genetic factors, pointing out that several of the genes involved in familial PD also are implicated in cancer [617][618][619].…”

Section: Cancermentioning

confidence: 99%

Epidemiology and etiology of Parkinson’s disease: a review of the evidence

et al. 2011

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“…A similar association of PD with decreased risk of almost all common cancers, including those that are strongly related to smoking (lung, colorectal and bladder cancer), was reported in 2007. [102,103] There were two notable exceptions: melanoma and breast carcinoma that were actually more common in patients with PD than in age-matched controls. Similarly, in individuals with Down syndrome aged over 30 years, the risk of leukaemia (specifically, acute myeloid leukaemia, but also acute lymphoblast leukaemia (ALL)) is significantly elevated, whereas the risk of most solid tumours (including breast cancer) is actually lower than the population risk.…”

Section: Cancer and Londd: Extremes Of A Wide Spectrum?mentioning

confidence: 99%