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Roll on genetics of PARK and Parkinsonism in the developing world
  1. Raj N Kalaria,
  2. Rufus Akinyemi
  1. Institute for Ageing and Health, Newcastle University, Newcastle upon Tyne, UK
  1. Correspondence to Professor Raj N Kalaria, Institute for Ageing and Health, Wolfson Research Centre, Campus for Ageing and Vitality, Newcastle upon Tyne NE4 5PL, UK; r.n.kalaria{at}ncl.ac.uk

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Ageing-related Parkinsonian syndromes and dementias with parkinsonism are recognised worldwide. However, knowledge on monogenic inheritance or genetics of these neurodegenerative disorders is meagre from the developing world.1 The remarkable progress within the last decade in the genetics of Parkinson's disease (PD) and disorders exhibiting parkinsonism has provided an impetus for genetic screening of these syndromes in different indigenous populations.2 Since the recognition of the α-synuclein gene, a staggering 15 PARK loci have been ascribed to autosomal dominant and recessive forms of PD (http://www.pdgene.org). In addition, mutations in unpredictably divergent genes such as the microtubule associated protein tau, glucocerebrosidase, PANK2 and PLA2G6 are attributed to parkinsonism in variants of the tauopathies, Gaucher's disease and Hallervorden–Spatz disease. The PARK genotypes, however, have not all been linked to proven Lewy body pathology or nigral degeneration2 as evident in dementia with Lewy bodies or PD with dementia (table 1). In this issue, Vinish et al3 provide interesting data on the profile of parkin mutations in North Indian subjects with PD (see page 166).

Table 1

Widely accepted dominant and recessive gene mutations linked to PD and screening in major regions of developing world

The parkin gene (PARK 2) is a causative gene (locus 6q25.2–27; OMIM 602544) implicated predominantly in recessive, early onset or juvenile PD. Over 100 parkin mutations ranging from single substitutions to exon duplications or deletions and spread over its 12 exons have been described. No specific genotype–phenotype patterns seem to emerge, given the variable rates of mutations in diverse populations worldwide. Parkin protein, ubiquitously expressed within neurons is an ubiquitin–E3 protein ligase involved in the ubiquitin–proteasome pathway. Parkin mutations likely result in loss of function through impaired ubiquitination of substrates and resultant accumulation of neurodegenerative elements. Therefore, it is pertinent to unravel the normal function of the protein, which also appears to be involved in mitochondrial replication. Notably, individuals with parkin mutations robustly respond to l-dopa therapy.

The frequency of parkin mutations of 40.5% in the study by Vinish et al3 is significantly higher than previously reported values of 7.2–12.5% from developing countries.2 Whereas studies from Sub-Saharan Africa did not find any pathogenic mutations in the parkin gene,4 the very high frequency of mutations in the current study is close to values reported among Europeans and may be due to the migrant origin of the ethnically homogenous North Indians. The homogenous deletions found in exons 1, 3 and 12 as well as a novel missense Gly1083Trp mutation are additional unique findings in this study and add to the increasing number of diverse parkin mutations in different populations. It is conceivable that PD patients and families in Sub-Saharan Africa and other developing countries (see table 1) are harbouring some as-yet uncovered novel parkin mutations or in other PARK loci. The finding of reduced parkin expression in lymphocyte cell lines is another unique discovery.3 It reveals the usefulness of blood biomarkers in detecting the risk of developing PD, especially in individuals with a significant family history. However, further studies in indigenous populations will no doubt enhance our understanding of the molecular dissection but more importantly the pathogenetic mechanisms of PD and thereby avail neuroprotective and therapeutic strategies.

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Footnotes

  • Linked articles 157255

  • Competing interests None.

  • Patient consent Obtained.

  • Provenance and peer review Commissioned; not externally peer reviewed.

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