Age-Mediated Transcriptomic Changes in Adult Mouse Substantia Nigra

Abstract

Substantia nigra pars compacta (SNpc) is highly sensitive to normal aging and selectively degenerates in Parkinson's disease (PD). Until now, molecular mechanisms behind SNpc aging have not been fully investigated using high throughput techniques. Here, we show early signs of aging in SNpc, which are more evident than in ventral tegmental area (VTA), a region adjacent to SNpc but less affected in PD. Aging-associated early changes in transcriptome were investigated comparing late middle-aged (18 months old) to young (2 months old) mice in both SNpc and VTA. A meta-analysis of published microarray studies allowed us to generate a common “transcriptional signature” of the aged (≥ 24 months old) mouse brain. SNpc of late-middle aged mice shared characteristics with the transcriptional signature, suggesting an accelerated aging in SNpc. Age-dependent changes in gene expression specific to SNpc were also observed, which were related to neuronal functions and inflammation. Future studies could greatly help determine the contribution of these changes to SNpc aging. These data help understand the processes underlying SNpc aging and their potential contribution to age-related disorders like PD.

Recombinant adenoassociated virus 2/5-mediated gene transfer is reduced in the aged rat midbrain

“…Due to the overlap between the steps of rAAV transduction (Schultz and Chamberlain, 2008) and the cellular processes affected by age (Gao et al , 2013; Lee, Weindruch, and Prolla, 2000; Ryazanov and Nefsky, 2002; Smith, Sun, and Sokoloff, 1995), it is reasonable to suggest that the aging brain environment alters the ability of rAAV2/5 to transduce neurons (Summarized in Figure 6). Specifically, in order to transduce a cell, rAAV2/5 must first bind to the N-linked sialic acid glycan receptor (Walters et al , 2001), platelet derived growth factor receptor (PDGFR) co-receptor (Di Pasquale et al , 2003), and possibly other receptors on the cell surface to initiate clathrin-mediated endocytosis of the rAAV5 capsid (Figure 6 step 1;Meier and Greber, 2004).…”

“…Aging is also known to impact transcription levels in the rodent SN (Gao et al , 2013), which would lead to decreased levels of viral genome transcription into mRNA (Figure 6 step 8). Thus, changes in transcription with age could potentially alter levels of other enzymes or proteins that are required for earlier stages of transduction, such as endocytosis or transport to the nucleus.…”

“…9) Transgene mRNA is translated into the protein encoded by the transgene. Numbers represent steps where viral transduction could be impeded by age-related cellular deficiencies (Bender et al, 2006; Blanpied, Scott, and Ehlers, 2003; D’Angelo et al , 2009; Gao et al, 2013; Kraytsberg et al, 2006; Park et al , 2001; Ryazanov and Nefsky, 2002; Sato et al , 2001; Sasaki et al , 2002; Smith, Sun, and Sokoloff, 1995). In the present set of experiments we demonstrate that robust deficits in exogenous transgene expression are associated with aging and that deficiencies leading to 4-fold less mRNA encoded by the transgene are primarily responsible for the diminished protein expression observed in the aged rats.…”

“…It is well established that certain cellular processes that are normally altered in the aged brain (D’Angelo et al, 2009; Gao et al, 2013; Lee, Weindruch, and Prolla, 2000;Ryazanov and Nefsky, 2002; Smith, Sun, and Sokoloff, 1995) are also utilized by viral vectors for transduction (Schultz and Chamberlain, 2008). The present study sought to determine whether viral vector-mediated transgene expression was reduced in the aged rat nigrostriatal system as compared to the young adult.…”

Selective accumulation of biotin in arterial chemoreceptors: requirement for carotid body exocytotic dopamine secretion

“…Total RNAs were isolated from CB, SCG and AM tissue with the RNeasy micro kit (Qiagen, Valencia, CA, USA) as previously described (Gao et al 2013). Due to the small size of the CB, cRNA was amplified using an Ambion WT expression kit (Life Technologies, Carlsbad, CA, USA).…”