Corticospinal motor neurons and related subcerebral projection neurons undergo early and specific neurodegeneration in hSOD1G93A transgenic ALS mice

P. Hande Özdinler, Susanna Benn, Ted H. Yamamoto, Mine Güzel, Robert H. Brown, Jeffrey D. Macklis

Research output: Contribution to journalArticle

93 Scopus citations

Abstract

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 nonmotor 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 nonmotor SCPN specifically and progressively degenerate in hSOD1G93A mice. Degeneration starts quite early and presymptomatically, by postnatal day 30. Other neocortical layers, cortical interneurons, and other projection neuron populations, even within layer V, are not similarly affected. Nonneuronal 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.

Original languageEnglish (US)
Pages (from-to)4166-4177
Number of pages12
JournalJournal of Neuroscience
Volume31
Issue number11
DOIs
StatePublished - Mar 16 2011

ASJC Scopus subject areas

  • Neuroscience(all)

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