Methyl-Arginine Profile of Brain from Aged PINK1-KO+A53T-SNCA Mice Suggests Altered Mitochondrial Biogenesis

Abstract

Hereditary Parkinson's disease can be triggered by an autosomal dominant overdose of alpha-Synuclein (SNCA) or the autosomal recessive deficiency of PINK1. We recently showed that the combination of PINK1-knockout with overexpression of A53T-SNCA in double mutant (DM) mice potentiates phenotypes and reduces survival. Now we studied brain hemispheres of DM mice at age of 18 months in a hypothesis-free approach, employing a quantitative label-free global proteomic mass spectrometry scan of posttranslational modifications focusing on methyl-arginine. The strongest effects were documented for the adhesion modulator CMAS, the mRNA decapping/deadenylation factor PATL1, and the synaptic plasticity mediator CRTC1/TORC1. In addition, an intriguing effect was observed for the splicing factor PSF/SFPQ, known to interact with the dopaminergic differentiation factor NURR1 as well as with DJ-1, the protein responsible for the autosomal recessive PARK7 variant of PD. CRTC1, PSF, and DJ-1 are modulators of PGC1alpha and of mitochondrial biogenesis. This pathway was further stressed by dysregulations of oxygen sensor EGLN3 and of nuclear TMPO. PSF and TMPO cooperate with dopaminergic differentiation factors LMX1B and NURR1. Further dysregulations concerned PRR18, TRIO, HNRNPA1, DMWD, WAVE1, ILDR2, DBNDD1, and NFM. Thus, we report selective novel endogenous stress responses in brain, which highlight early dysregulations of mitochondrial homeostasis and midbrain vulnerability.

Genetic mutations linked to Parkinson's disease differentially control nucleolar activity in pre-symptomatic mouse models

“…Because NCL is mainly localized in the dense fibrillar compartment where transcription and processing of rDNA take place, these steps of rRNA biogenesis might be altered in the hA53T-SNCA/PINK1KO mice (Sirri et al, 2008; Berger et al, 2015). A similar function is common to causative mutant proteins, for example, in polyglutamine diseases (Parlato and Bierhoff, 2015; Tsoi et al, 2012). However, based on this study, we cannot rule out the possibility that the hA53T-SNCA mutation is responsible for the altered nucleolar activity and integrity observed at 3 and 20 months.…”

“…Nucleolar stress is emerging as one important factor in neurodegenerative diseases (Hetman and Pietrzak, 2012; Parlato and Bierhoff, 2015). In general, for as yet unclear reasons, inhibition of rRNA synthesis could be both neuroprotective and neurotoxic (Kreiner et al, 2013).…”

“…Accordingly, reduced rDNA transcription and disruption of nucleolar integrity are common to several neurodegenerative disorders (Grummt, 2013; Parlato and Kreiner, 2013). Interestingly, mutant proteins and RNAs may directly interfere with the RNA polymerase I machinery, reducing the level of rDNA transcription in polyglutamine diseases, including Huntington's disease (HD) and in some forms of amyotrophic lateral sclerosis and fronto-temporal dementia (ALS/FTD) (Parlato and Bierhoff, 2015). …”

Schizophrenia: neuroinflammation, neurodegeneration or neurodevelopment? A genetic overview

“…Authors described altered methylation pattern at sites previously associated with degeneration disorder, such as Hnrnpa1 gene (hypomethylated), regulated together with stressinduced phosphorylation signals. Some mutations have already been associated with amyotrophic lateral sclerosis and frontotemporal dementia 10 . GWAS performed in association with cognitive measures in schizophrenia have not showed any significant SNP for cognitive impairment in the disease, but a polygenic score with little variance explanation.…”

Iron Depletion Reduces Abce1 Transcripts While Inducing the Mitophagy Factors Pink1 and Parkin

“…Mitophagy is relevant for only a few among hundreds or thousands of mitochondria per cell at any given time, and the accumulation of iron is an insidious process over decades in PD patients, so the compensatory efforts needed are minimal. Therefore, global expression profiles of Pink1 -/-mouse brain showed only subtle evidence of deficient mitophagy and altered mitochondrial biogenesis [16,[27][28][29], the dysregulated expression of heme-related transcripts Hmox1 and Hebp1 was noted only upon culture of mouse Pink1 -/-primary cortical neurons [29], and limited survival of the Pink1 -/-mouse was observed only after additional overexpression of toxic alpha-synuclein [16,30]. In general, Pink1-and Parkin-deficient mice show signs of altered mitophagy and neurodegeneration only in the presence of further stressors such as mitochondrial mutations, exhaustive exercise or bacterial infections [31][32][33][34].…”