To explore what influences motor neuron function prior to neurodegeneration, Mentis et al. (2011) examined the primary afferent input and found that loss of
synaptic input from sensory spindle afferents followed the temporal and topographic pattern of later motor neuron loss. Treatment with a histone deacetylase inhibitor, an intervention that improves motor function in this mouse model, also improved synaptic input from muscle spindle afferents (Mentis et al., 2011). Since a treatment that prevents reduction of the muscle MK-2206 manufacturer spindle afferents also ameliorated motor neuron loss, this paper suggests that that loss of afferent input may contribute to eventual motor neuron degeneration in SMA. A second example of decreased synaptic input contributing to neurodegeneration involves the spinocerebellar ataxias (SCAs), a group of neurodegenerative
disorders that predominantly affect neurons in the brainstem and cerebellum involved in motor coordination and balance. Spinocerebellar ataxia type 1 (SCA1) Bcl-2 protein family is a CAG repeat disorder characterized by a selective degeneration of cerebellar Purkinje cells (PCs). PCs receive excitatory synaptic input from two cell types, cerebellar granule neurons and inferior olive (IO) neurons, whose climbing fibers (CFs) synapse on PC dendrites in the cerebellar molecular layer. It has recently been reported that CF input is reduced well before PC degeneration occurs in several mouse models of SCA1 (Barnes et al., 2011 and Duvick et al., 2010). Furthermore, using a conditional expression system, one study found that the effect of
the disease gene on CF input occurs during the first 5 postnatal weeks (Barnes et al., 2011). When disease gene expression was prevented during this early period, loss in CF input was partially reversed and PC degeneration was completely prevented (Barnes et al., 2011). Since expression of mutant ataxin-1 in this model is selectively restricted to PCs, the interaction between CF and PC neurons must be occurring in a bidirectional fashion. Thus, PCs expressing mutant protein prevent normal Electron transport chain synaptic structure and function of CFs, through an unknown signaling mechanism, and subsequent CF dysfunction early in the course of disease contributes to the eventual PC degeneration. Additional evidence for the importance of CF input to PC survival comes from the study of spinocerebellar ataxia type 7 (SCA7), another polyglutamine expansion disorder (Garden and La Spada, 2008). Both cerebellar PCs and IO neurons are among the selectively vulnerable populations in SCA7. When SCA7 was modeled in mice via transgenic expression of human mutant ataxin-7 protein, evidence for non-cell-autonomous degeneration of cerebellar PCs was noted early on. One group directed expression of the mutant gene specifically to PCs and did not observe significant pathology (Yvert et al., 2000).