Amyotrophic lateral sclerosis (ALS) is characterized by predominant vulnerability and central degeneration of both corticospinal/corticobulbar motor neurons (CSMN; “upper motor neurons”) in cerebral cortex, and spinal/bulbar motor neurons (SMN; “lower motor neurons”) in spinal cord and brainstem. Increasing evidence indicates broader cerebral cortex pathology in cognitive, sensory, and association systems in select cases. It remains unclear whether widely-accepted transgenic ALS models, in particular hSOD1G93A mice, undergo degeneration of CSMN and molecularly/developmentally closely related populations of non-motor projection neurons (e.g. other subcerebral projection neurons (SCPN)), and whether potential CSMN/SCPN degeneration is specific and early. This relative lack of knowledge regarding “upper motor neuron” pathology in these ALS model mice has hindered both molecular-pathophysiologic understanding of ALS, and their use toward potential CSMN therapeutic approaches. Here, using a combination of anatomic, cellular, transgenic labeling, and newly available neuronal subtype-specific molecular analyses, we identify that CSMN and related non-motor SCPN specifically and progressively degenerate in hSOD1G93A mice. Degeneration starts quite early and presymptomatically, by P30. Other neocortical layers, cortical interneurons, and other projection neuron populations, even within layer V, are not similarly affected. Non-neuronal pathology in neocortex (activated astroglia and microglia) is consistent with findings in human ALS cortex, and in affected mouse and human spinal cord. These results indicate previously unknown neuron type-specific vulnerability of CSMN/sensory and association SCPN, and identify that characteristic dual CSMN and SMN degeneration is conserved in hSOD1G93A mice. These results provide a foundation for detailed investigation of CSMN/SCPN vulnerability, and toward potential CSMN therapeutics in ALS.

Peripheral nerve transection results in the rapid death by apoptosis of neonatal but not adult sensory and motor neurons. We show that this is due to induction and phosphorylation in all adult axotomized neurons of the small heat shock protein Hsp27 and the failure of such induction in most neonatal neurons. In vivo delivery of human Hsp27 but not a nonphosphorylatable mutant prevents neonatal rat motor neurons from nerve injury-induced death, while knockdown in vitro and in vivo of Hsp27 in adult injured sensory neurons results in apoptosis. Hsp27's neuroprotective action is downstream of cytochrome c release from mitochondria and upstream of caspase-3 activation. Transcriptional and posttranslational regulation of Hsp27 is necessary for sensory and motor neuron survival following peripheral nerve injury.

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Developing neurons are programmed to die by an apoptotic pathway unless they are rescued by extrinsic growth factors that generate an anti-apoptotic response. By contrast, adult neurons need to survive for the lifetime of the organism, and their premature death can cause irreversible functional deficits. The default apoptotic pathway is shut down when development is complete, and consequently growth factors are no longer required to prevent death. To protect against accidental apoptotic cell death, anti-apoptotic mechanisms are activated in mature neurons in response to stress. Loss or reduced activity of these intrinsic anti-apoptotic 'brakes' might contribute to or accelerate neurodegeneration, whereas their activation might rescue neurons from injury or genetic abnormalities.