Phenotypic variability of PINK1 expression: 12 Years' clinical follow-up of two Italian families

Ricciardi, Lucia; Petrucci, Simona; Guidubaldi, Arianna; Ialongo, Tàmara; Serra, Laura; Ferraris, Alessandro; Spanò, Barbara; Bozzali, Marco; Valente, Enza Maria; Bentivoglio, Anna Rita

doi:10.1002/mds.25994

Cited by 51 publications

(50 citation statements)

References 39 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This means that, in our experimental model, HET individuals were expected to be less cognitively impaired than HOM patients. However, consistent with a previous study on PINK1 mutation carriers (including part of the patients enrolled here) [12], all but one subjects from either group (HET, HOM) reported pathological scores at MoCA. Moreover, the two cognitively preserved individuals were both PINK1 heterozygous carriers, while all Park2 mutation carriers (3 HET, 2 HOM) showed pathological scores at MoCA.…”

Section: Discussionsupporting

confidence: 91%

“…In the HET group, two PINK1 carriers received a diagnosis of possible PD (subjects F1-IV:13/M and F1-IV:12/M, already reported in a previous publication) [12]. …”

Section: Resultsmentioning

confidence: 99%

“…On the other hand, other studies have described cognitive impairment in patients with Park2 mutations [11], as well as non-specific cognitive deficits in healthy heterozygous carriers [10]. We recently published neuropsychological data from PINK1 homozygous and heterozygous mutation carriers followed-up for 12 years, based on the Montreal Cognitive Assessment battery (MoCA) and an extensive battery exploring all principal cognitive domains [12]. Interestingly, all affected homozygotes and 5 out of 14 heterozygotes reported abnormal scores at the MoCA and at tests sensitive to frontal dysfunction, consistently with the dysexecutive syndrome which is typically observed in sporadic PD [13].…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Brain Connectivity Changes in Autosomal Recessive Parkinson Disease: A Model for the Sporadic Form

et al. 2016

Self Cite

View full text Add to dashboard Cite

Biallelic genetic mutations in the Park2 and PINK1 genes are frequent causes of autosomal recessive PD. Carriers of single heterozygous mutations may manifest subtle signs of disease, thus providing a unique model of preclinical PD. One emerging hypothesis suggests that non-motor symptom of PD, such as cognitive impairment may be due to a distributed functional disruption of various neuronal circuits. Using resting-state functional MRI (RS-fMRI), we tested the hypothesis that abnormal connectivity within and between brain networks may account for the patients’ cognitive status. Eight homozygous and 12 heterozygous carriers of either PINK1 or Park2 mutation and 22 healthy controls underwent RS-fMRI and cognitive assessment. RS-fMRI data underwent independent component analysis to identify five networks of interest: default-mode network, salience network, executive network, right and left fronto-parietal networks. Functional connectivity within and between each network was assessed and compared between groups. All mutation carriers were cognitively impaired, with the homozygous group reporting a more prominent impairment in visuo-spatial working memory. Changes in functional connectivity were evident within all networks between homozygous carriers and controls. Also heterozygotes reported areas of reduced connectivity when compared to controls within two networks. Additionally, increased inter-network connectivity was observed in both groups of mutation carriers, which correlated with their spatial working memory performance, and could thus be interpreted as compensatory. We conclude that both homozygous and heterozygous carriers exhibit pathophysiological changes unveiled by RS-fMRI, which can account for the presence/severity of cognitive symptoms.

show abstract

Section: Discussionsupporting

confidence: 91%

“…In the HET group, two PINK1 carriers received a diagnosis of possible PD (subjects F1-IV:13/M and F1-IV:12/M, already reported in a previous publication) [12]. …”

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Brain Connectivity Changes in Autosomal Recessive Parkinson Disease: A Model for the Sporadic Form

et al. 2016

Self Cite

View full text Add to dashboard Cite

show abstract

“…Careful analysis of families with mutations in recessive Parkinson’s disease genes revealed that heterozygous mutation carriers may also develop mild parkinsonism (Criscuolo et al , 2006; Klein et al , 2007; Eggers et al , 2010; Ricciardi et al , 2014). In a few instances, a seemingly autosomal dominant mode of inheritance was found in heterozygous carriers of mutations in recessive Parkinson’s disease genes (Klein et al , 2007).…”

Section: Introductionmentioning

confidence: 99%

Heterozygous PINK1 p.G411S increases risk of Parkinson’s disease via a dominant-negative mechanism

Puschmann

Fiesel

Caulfield

et al. 2016

Brain

125

103

View full text Add to dashboard Cite

See Gandhi and Plun-Favreau (doi:) for a scientific commentary on this article.Heterozygous mutations in recessive Parkinson’s disease genes have been postulated to increase disease risk. Puschmann et al. report a genetic association between heterozygous PINK1 p.G411S and Parkinson’s disease. They provide structural and functional explanations for a partial dominant-negative effect of the mutant protein, which impairs wild-type PINK1 activity through hetero-dimerization.

show abstract

“…Mitochondrial dysfunction likely plays a central role in this process, although its underlying mechanisms are poorly understood (Haddad and Nakamura, 2015). Mutations in PTEN-induced putative kinase 1 (PINK1) cause rare inherited forms of PD (Valente et al, 2004; Ricciardi et al, 2014), providing the first direct genetic evidence that mitochondrial dysfunction can cause PD. Heterozygous mutations in PINK1 are also a risk factor for sporadic PD (Puschmann et al, 2017).…”

Section: Introductionmentioning

confidence: 99%

Long-term oral kinetin does not protect against α-synuclein-induced neurodegeneration in rodent models of Parkinson's disease

Orr

Rutaganira

Roulet

et al. 2017

Neurochemistry International

View full text Add to dashboard Cite

Mutations in the mitochondrial kinase PTEN-induced putative kinase 1 (PINK1) cause Parkinson's disease (PD), likely by disrupting PINK1's kinase activity. Although the mechanism(s) underlying how this loss of activity causes degeneration remains unclear, increasing PINK1 activity may therapeutically benefit some forms of PD. However, we must first learn whether restoring PINK1 function prevents degeneration in patients harboring PINK1 mutations, or whether boosting PINK1 function can offer protection in more common causes of PD. To test these hypotheses in preclinical rodent models of PD, we used kinetin triphosphate, a small-molecule that activates both wild-type and mutant forms of PINK1, which affects mitochondrial function and protects neural cells in culture. We chronically fed kinetin, the precursor of kinetin triphosphate, to PINK1-null rats in which PINK1 was reintroduced into their midbrain, and also to rodent models overexpressing α-synuclein. The highest tolerated dose of oral kinetin increased brain levels of kinetin for up to 6 months, without adversely affecting the survival of nigrostriatal dopamine neurons. However, there was no degeneration of midbrain dopamine neurons lacking PINK1, which precluded an assessment of neuroprotection and raised questions about the robustness of the PINK1 KO rat model of PD. In two rodent models of α-synuclein-induced toxicity, boosting PINK1 activity with oral kinetin provided no protective effects. Our results suggest that oral kinetin is unlikely to protect against α-synuclein toxicity, and thus fail to provide evidence that kinetin will protect in sporadic models of PD. Kinetin may protect in cases of PINK1 deficiency, but this possibility requires a more robust PINK1 KO model that can be validated by proof-of-principle genetic correction in adult animals.

show abstract

Phenotypic variability of PINK1 expression: 12 Years' clinical follow-up of two Italian families

Abstract: We expanded the phenotypic profile of PINK1-related parkinsonism, including psychiatric and cognitive features as part of clinical presentation.

Cited by 51 publications

References 39 publications

Brain Connectivity Changes in Autosomal Recessive Parkinson Disease: A Model for the Sporadic Form

Brain Connectivity Changes in Autosomal Recessive Parkinson Disease: A Model for the Sporadic Form

Heterozygous PINK1 p.G411S increases risk of Parkinson’s disease via a dominant-negative mechanism

Long-term oral kinetin does not protect against α-synuclein-induced neurodegeneration in rodent models of Parkinson's disease

Contact Info

Product

Resources

About