Prof. Don W. Cleveland

Prof. Cleveland

ISP2012 Symposium Talk Abstract:

Mechanism and therapy in neurodegenerative disease: ALS and beyond

The great cell biologists of the 19th century, especially Virchow and Bernard, established the pivotal idea that individual cells function autonomously, while being part of the whole organism. Since then the major neurodegenerative diseases have traditionally been considered mechanistically cell autonomous, meaning that damage within a selective population of affected neurons alone suffices to produce disease. Most of the genes whose mutation is now known to cause the major neurodegenerative diseases are widely or ubiquitously expressed, however, including superoxide dismutase (SOD1) whose mutation causes an inherited form of the fatal, adult motor neuron disease ALS. Modeling in mice has demonstrated that disease mechanism is through an acquired toxicity unrelated to dismutase activity. Use of selective gene excision or viral encoded siRNA has demonstrated that toxicity is non-cell autonomous, with mutant SOD1 within motor neurons and oligodendrocytes driving disease onset, while damage within neighboring astrocytes and microglia accelerates disease progression.

These findings have validated therapies to slow disease progression, including cell replacement through injection of stem cell derived astrocytic progenitors. Another approach now in trial is suppression of mutant SOD1 expression following infusion of DNA antisense oligonucleotides (ASOs) that direct destruction of SOD1 mRNA widely within the non-human primate nervous system. Moreover, because non-cell autonomous toxicity is likely to be generally true in neurodegenerative disease, ASO infusion to target catalytic degradation of specific mRNAs may prove to be a broadly applicable therapeutic approach. For example, polyglutamine expansion in the widely expressed huntingtin protein is the sole cause of Huntington's disease (HD). Infusion into rodents or non-human primates of ASOs targeting huntingtin mRNA effectively lowers huntingtin levels in the striatum and cortex, the primary brain targets of HD pathology. Transient infusion of ASOs into already symptomatic HD mouse models not delays disease progression, but mediates a sustained reversal of disease phenotype that persists for much longer than the huntingtin knockdown. Rather than requiring continuous treatment, these findings establish a feasible therapeutic strategy for sustained HD disease reversal from a “Huntingtin holiday” produced by transient ASO therapy.

Finally, a unifying feature of many neurodegenerative diseases has come from the cytoplasmic misaccumulation of TDP-43, an RNA/DNA binding protein. This is especially so in ALS and in Frontal Temporal Dementia (FTD) Discovery that mutations in TDP-43 cause dominantly inherited ALS and that TDP-43 is misaccumulated in essentially all instances of sporadic ALS has initiated a paradigm shift in defining disease mechanism. So what does TDP-43 do in the nervous system? TDP-43 has binding sites on mRNAs from 6,304 genes, and loss of nuclear TDP-43 (that is seen in neurons of sporadic ALS patients) affects the levels of >600 mRNAs and splicing patterns of 965 mRNAs. RNAs whose levels are most depleted by reduction in TDP-43 are derived from genes with very long introns and which encode proteins involved in synaptic activity, providing a basis for neuronal vulnerability to loss of TDP-43 function. Finally, TDP-43 enhances splicing of an intron within the 3' untranslated region of its own mRNA thereby triggering nonsense mediated RNA degradation, thereby providing a mechanism by which cytoplasmic aggregation will drive runaway synthesis of TDP-43 following any initiating insult that reduces nuclear TDP-43 activity.

Prof. Cleveland's ISP2012 Lecture
Understanding ALS: from mechanism to therapy
Prof. Cleveland's ISP2012 Profile
Prof. Cleveland's UCSD Profile:
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ISP2012 Abstracts