Mounting evidence is linking neurodegenerative disorders, such as Parkinsonism and dementia, with mitochondrial dysfunction.1 At the 5th Annual Congress of the European Academy of Neurology (EAN) in Oslo, Norway, the genetic basis of mitochondrial Parkinsonism was further elucidated with new findings.
Mitochondrial dysfunction has been associated with a wide-ranging clinical spectrum, from pure myopathy to complex multi-system conditions affecting both the peripheral and the central nervous systems.1 Mutations in nuclear genes encoding proteins involved in mitochondrial DNA replication, turn-over, and dynamics, have been associated with chronic progressive external ophthalmoplegia (CPEO) and age-related Parkinsonism.1 A common emerging theme appears to be disturbed mitochondrial (mt) DNA maintenance, leading to disturbed neuronal energy metabolism and eventual neurodegeneration.2, 3
In the study presented by Dr La Morgia (Bologna, Italy) at EAN 20192, mutations in both nuclear as well as mtDNA were examined in the context of familial Parkinsonism. Among ten families, mutations were identified in known genes associated with mitochondrial dysfunction: POLG, TWNK, OPA1 and DGUOK, all of which are nuclear genes associated with mtDNA replication. In addition, novel mutations were described in SLC25A4, which encodes the protein adenine nucleotide translocase 1 (ANT1), important in mitochondrial energy production. Novel mutations were also described in RNASEH1, which encodes a protein (endonuclease) that breaks down the RNA in RNA-DNA hybrids. These findings reinforce the link between familial Parkinsonism and mutations in nuclear genes involved in mitochondrial DNA maintenance and replication.
Dr La Morgia and co-authors also reported on six families with Parkinsonism carrying previously uncharacterised point mutations in mtDNA itself. These mutations were primarily in tRNAs involved in the process of protein translation. While these mtDNA mutations had not been previously associated with CPEO or Parkinsonism, they have been linked to other disorders such as mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS).
The findings of Dr La Morgia and colleagues expand on our knowledge of the genetic background of CPEO and Parkinsonism, and elucidate the multiple ways in which both nuclear and mitochondrial DNA mutations can disturb neuronal energy balance. Moreover, considering the mtDNA mutations have been documented in dopaminergic neurons of the substantia nigra in patients with idiopathic Parkinson’s diseases,1 further links between mtDNA mutations and neurodegeneration are likely to be characterised in the future.
- Carelli V. et al. Syndromic Parkinsonism and dementia associated with OPA1 missense mutation. Ann Neurol. 2015;78:21–38.
- La Morgia C. et al. Parkinsonism in mitochondrial diseases: expanding the genetic basis of an emerging clinical phenotype of mitochondrial dysfunction. Presented at the 5th annual congress of the European Association of Neurology, 29 June 2019.
- Turnbull H.E. et al. The mitochondrial brain: From mitochondrial genome to neurodegeneration. Biochim Biophys Acta. 2010;1802(1):111–121.