Fig. 3.

Time-line of pathological and clinical changes in the high-expressor hSOD1^G93A line of transgenic mice. The most important and earliest abnormalities reported for the hSOD1^G93A transgenic mouse model are shown. Months before motor neurons degenerate and clinical symptoms appear (P90), widespread and early onset of pathological abnormalities are detected in this ALS mouse model. See references stated here and text for additional information. (Ref. 1 SOD1 expression is detected from embryonic (E) day 8.5 (E8.5) [Yon et al., 2008]). (Ref. 2 Temporal behavioral abnormalities during early postnatal (P) development: P2–4 mSOD1^G93A mice show reduced forelimb placing and righting capacities [van Zundert et al., 2008]. Similar reversible sensorimotor alterations are observed for neonatal (P1–P7) hSOD1^G85R mice [Amendola et al., 2004]). (Ref. 3 Electrical abnormalities in hSOD1^G93A motor neurons (MNs) at P4–P10; hypoglossal motor neurons (HMs) display increased excitability and PC_Na [van Zundert et al., 2008]. hSOD1^G93A spinal cord motor neurons also possess enhanced PC_Na (P0–P12)and PC_Ca(P6–P12) [Quinlan et al., 2011]. In addition, early (P6–P10) abnormal changes in electrical properties, including in excitability, are detected in the low-expressor hSOD1^G93A transgenic line and the hSOD1^G85R mutant mice [Bories et al., 2007; Pambo-Pambo et al., 2009]). (Ref. 4 Synaptic transmission mediated by AMPA, NMDA and glycine-receptors is altered for HMs in P4–10 hSOD1^G93A mice [van Zundert et al., 2008]). (Ref. 5 Morphological abnormalities of motor neurons of hSOD1^G93A mice at P6; precocious remodeling of HMs [van Zundert et al., 2008]. Early (P6–P10) abnormal dendritic branching is also observed for hSOD1^G85R transgenic mice [Amendola and Durand, 2008]). (Ref. 6 Genes involved in stress-related pathways are transiently upregulated between P12 and P26, in vulnerable hSOD1^G93A spinal motor neurons [Saxena et al., 2009]). (Ref. 7 Ultrastructural alterations of motor neurons in mSOD1^G93A mice, starting at P14 (2 weeks); mitochondria swellings and small vacuoles are present in distal dendrites and in the cell bodies of spinal cord motor neurons [Bendotti et al., 2001]). (Ref. 8 mutant SOD1 aggregates in spinal motor neurons of hSOD1^G93A mice at P30 [Johnston et al., 2000]). (Ref. 9 Genes involved in UPR and in the ubiquitin proteasome system (UPS) are up- and down-regulated, respectively, in vulnerable P32 spinal motor neurons of hSOD1^G93A mice [Saxena et al., 2009]). (Ref. 10 Functional loss of motor unit for fast-twitch hind-limb muscles (medial gastrocnemius [MG]) is detected starting at P40in hSOD1^G93A mice [Hegedusetal., 2007]). (Ref. 11 DNA damage (e.g., immunohistochemistry (ICH) with antibodies recognizing single-stranded breaks) is detected in motor neurons of hSOD1^G93A mice, starting at P49 (7 weeks) [Martin et al., 2007]). (Ref. 12 Structural changes in motor units of hSOD1^G93A mice starting at P50; loss of MG neuromuscular synapses and prominent vacuolation in nerve terminals [Frey et al., 2000]). [Ref. 13 Markers of apoptosis (including caspases 1 and 3) in motor neurons are detected as of P60 in spinal cord motor neurons of hSOD1^G93A mice [Li et al., 2000]. See Martin et al., [2007] for discussion on apoptotic-necrotic hybrid forms of motor neuron death in ALS]. (Ref. 14 Degeneration of motor neurons (e.g., those that display choline acetyltransferas (Chat)-positive IRR)of hSOD1^G93A mice starts at ∼P90 [Chiu et al., 1995]). (Ref. 15 Clinical symptoms (e.g., small tremors, weight lose) [Chiu et al., 1995] and more prominent behavioral abnormalities (e.g., decline in hanging test and rotarod performance) of hSOD1^G93A mice starts at ∼P90). See also additional reviews for deficits during development in other mutant SOD1 mice, including the low-expressor hSOD1^G93A, hSOD1^G85R, and hSOD1^G127X mice [Durand et al., 2006; Elbasiouny et al., 2010b; Quinlan, 2011].