Microarray analysis of the cellular pathways involved in the adaptation to and progression of motor neuron injury in the SOD1 G93A mouse model of familial ALS - PubMed (original) (raw)

Figure 3.

A, Motor neurons isolated from G93A mice at 60 d show upregulation in several classes of genes delineating what is likely to be happening in these cells under stress. There is upregulation of the transcriptional machinery, along with upregulation of translation-related ribosomal and folding proteins, as the motor neuron attempts to compensate for the ongoing cellular stress. All these mechanisms require ATP, provoking a massive increase in the work load of mitochondria, leading to upregulation of carbohydrate metabolism and respiratory chain activity, which in turn causes increased ROS production. The observed imbalance among the subunits forming the ATP synthase complex, shown by downregulation of the δ subunit, will generate additional oxidative stress, with consequent production of oxidized proteins. These are then ubiquitinated and targeted for proteasomal degradation. B, Over time, the accumulation of damaged proteins and ROS is likely to cause a general collapse in cellular functioning, leading to downregulation of the compensatory pathways previously activated and leaving the cell with decreased energy and protein turnover. The cell increases protein degradation functions, with activation of the lysosomal machinery. Production and secretion of some subunits of the complement cascade are important signals of cellular stress for neighboring cells. The final abortive attempt at survival comes through activation of the cell cycle, with upregulation of cyclin L1 (involved in the transition from the quiescent state, G0, to the first phase of the cell cycle, G1) and cyclins D2 and E2 (involved in the progression of the cell cycle through G1 phase). The upregulation of cyclin I suggests that motor neurons are trying to exercise negative control on the transition between the G1 and S phase to prevent the abnormal progression through the cell cycle. Atf4, Activating transcription factor 4; Atp5a1, ATP synthase F1 complex α1 subunit; Atp5d, ATP synthase F1 complex δ subunit; Cct4, chaperonin subunit 4; Ctsz, cathepsin-Z; Eef1, eukaryotic translation elongation factor 1; Eif3, eukaryotic translation initiation factor 3; Hsp, heat shock protein; Lyz, lysozyme; Lzp-s, P-lysozyme structural; Mdh1, malate dehydrogenase 1; Ndn, necdin; Psmc6, proteasome 26S; Rpl, ribosomal protein L; Sdha, succinate dehydrogenase complex subunit A; Taf9, transcription activator factor 9; Tcerg1, transcription elongation regulator 1 (CA150); Tgfb1i4, transforming growth factor β1-induced transcript 4; Ube1c, ubiquitin-activating enzyme E1C; Uble1b, ubiquitin-like activating enzyme E1B; Usp36, ubiquitin-specific preotease 36; H+, hydrogen ion; TCA, tricarboxylic acid.