Malfunctioning DNA Damage Response (DDR) Leads to the Degeneration of Nigro-Striatal Pathway in Mouse Brain

Abstract

Pronounced neuropathology is a feature of ataxia-telangiectasia (A-T) and Nijmegen breakage syndrome (NBS), which are both genomic instability syndromes. The Nbs1 protein, which is defective in NBS, is a component of the Mre11/RAD50/NBS1 (MRN) complex. This complex plays a major role in the early phase of the cellular response to double strand breaks (DSBs) in the DNA. Among others, MRN is required for timely activation of the protein kinase ATM (A-T mutated), which is disrupted in patients with A-T. Earlier reports show that Atm-deficient mice exhibit severe degeneration of tyrosine hydroxylase (TH)-positive dopaminergic nigro-striatal neurons and their terminals in the striatum. This cell loss is accompanied by a large reduction in immunoreactivity for the dopamine transporter protein (DAT) in the striatum. To test whether Nbs1 inactivation also affects the integrity of the nigro-striatal pathway, we examined this pathway in a murine model with conditional inactivation of the Nbs1 gene in central nervous system (Nbs1-CNS-Δ). We report that this model has a reduction in TH-positive cells in the substantia nigra. This phenomenon was seen at very early age, while Atm-/- mice showed a progressive age-dependent reduction. Furthermore, we observed an age-dependent increase in the level of TH in the striatum of Atm-/- and Nbs1-CNS-Δ mice. In addition to the altered expression of TH, we also found a reduction of DAT in the striatum of both Atm-/- and Nbs1-CNS-Δ mice at 60 days of age. Finally, microglial recruitment and alterations in the levels of various neurotrophic factors were also observed. These results indicate that malfunctioning DNA damage response severely affects the integrity of the nigro-striatal pathway and suggest a new neurodegenerative pathway in Parkinsonian syndromes.

Analysis of Clinical and Genetic Characterization of Three Ataxia–Telangiectasia Pedigrees With Novel ATM Gene Mutations

“…Given the heterogeneity of clinical presentation at the onset of AT, our study also suggests that, in rare cases, ataxia may be masked by generalized dystonia, which may be the initial and most prominent neurological manifestation in patients with classical AT. The neuropathological mechanism is not fully understood, but it may be due to the severe degeneration of the basal ganglia, mainly dopaminergic neurons in the substantia nigra, affecting the integrity of the nigro-striatal pathway and leading to premature and severe dopamine uptake dysfunction ( 16 , 20 ). In addition, cerebellar atrophy and cerebellar dysfunction may induce and exacerbate dystonia ( 21 ).…”

DNA Damage-Mediated Neurotoxicity in Parkinson’s Disease

“…In PD, the pathogenicity of DNA damage is not only enhanced by its association with typical PD pathology, but also by the fact that DNA damage accumulation occurs before the onset of PD, implying its direct involvement in the pathophysiology [ 18 , 19 , 20 ]. More importantly, the loss of function of specific DNA repair proteins in mice can recapitulate part of the disease phenotype of PD, and some proteins known to play key roles in PD have been shown to directly mediate DNA repair [ 14 , 21 , 22 , 23 , 24 , 25 ]. All this evidence suggests that DNA damage may be the direct mechanism of neurodegeneration in PD.…”

Nuclear DJ-1 Regulates DNA Damage Repair via the Regulation of PARP1 Activity

“…On the other hand, DNA damage has been shown to be associated with PD pathology in mouse models of the disease [16][17][18]. More importantly, mice lacking DNA repair proteins can recapitulate some of the disease phenotype of PD [9,[18][19][20]. For instance, mice lacking ATM, an essential part of DSB repair, exhibited PD-like motor abnormalities, as well as reduced expression of tyrosine hydroxylase and dopamine transporters [19,21].…”