Glial cells as intrinsic components of non-cell-autonomous neurodegenerative disease

Abstract

A lesson from dominantly inherited forms of diverse neurodegenerative diseases, including amyotrophic lateral sclerosis, spinocerebellar ataxia and Huntington's disease, is that the selective dysfunction or death of the neuronal population most at risk in each disease is not mediated solely by damage from the mutant protein within the target neurons. The disease-causing toxic process, which in each case is caused by mutation in a gene that is widely or ubiquitously expressed, involves damage done by mutant proteins within the non-neuronal glial cells of the central nervous system, especially astrocytes and microglia. The disease mechanism is non-cell-autonomous, with toxicity derived from glia as a prominent contributor driving disease progression and in some instances even disease initiation.

Figure 1

Insights from animal models of diverse human neurodegenerative diseases suggest that disease mechanisms are non-cell autonomous requiring the convergence of damage within the vulnerable neurons and their neighboring glial cells. Glial-derived toxicity can strongly influence disease progression (e.g. in ALS^,) or can even contribute to disease initiation (e.g. in SCA^,). Glutamate (Glu) mediated excitotoxicity is a prime example of neuron-glial toxicity that has been proposed to be a significant component in ALS^,, SCA^, and HD^,.

Figure 2

Non-cell autonomous neurotoxicity in ALS. (a) Selective mutant SOD1 silencing demonstrated that mutant damage within motor neurons drives disease initiation^,,, while mutant expression within neighboring microglia underlies rapid disease progression^,. The in vivo contributions of mutant SOD1 expression in astrocytes or Schwann cells are not yet established, while mutant expression in muscle does not contribute to disease. Consistent with non-cell autonomous mechanisms, selective mutant expression in either motor neurons^, (b), astrocytes (c) or microglia (d) alone are not sufficient to induce motor neuron degeneration.

Figure 3

Non-cell autonomous, glial derived toxicity can lead to degeneration of Purkinje neurons in SCA7. Although moderate Purkinje cell degeneration can be induced by neuronal expression of mutant ataxin-7 (a), expression of mutant ataxin-7 in neurons and glia, but not the Purkinje neurons themselves (b), or in the astrocytic Purkinje cell associated Bergmann glia alone (c), is sufficient to provoke Purkinje cell degeneration.