The Epigenetics of Stroke Recovery and Rehabilitation: From Polycomb to Histone Deacetylases

Abstract

Classical de-afferentation studies, as well as experience-dependent visual plasticity paradigms, have confirmed that both the developing and adult nervous system are capable of unexpected levels of plasticity. This capacity is underscored by the significant spontaneous recovery that can occur in patients with mild-to-moderate impairment following stroke. An evolving model is that an interaction of biological and environmental factors during all epochs post-stroke influences the extent and quality of this plasticity. Here, we discuss data that have implicated specific epigenetic proteins as integrators of environmental influences in 3 aspects of stroke recovery: spontaneous impairment reduction in humans; peri-infarct rewiring in animals as a paradigm for developing therapeutically-driven impairment reduction beyond natural spontaneous recovery; and, finally, classical hippocampal learning and memory paradigms that are theoretically important in skill acquisition for both impairment reduction and compensatory strategies in the rehabilitation setting. Our discussion focuses primarily on B lymphoma Mo-MLV1 insertion region proteins of the polycomb repressive complex, alpha thalassemia/mental retardation syndrome X-linked chromatin remodeling factors, and the best known and most dynamic gene repressors, histone deacetylases. We will highlight exciting current data associated with these proteins and provide promising speculation about how they can be manipulated by drugs, biologics, or noninvasive stimulation for stroke recovery.

Stroke Recovery Genetics

“…Epigenetic mechanisms regulating the DNA transcription have a potential role in stroke recovery and can modulate several downstream pathways-for review see Elder et al 62 Micro-RNA in an ischemic brain area can be up-and downregulated during different time points of the spontaneous recovery phase of ischemic stroke, 53 indicating how different biochemical pathways are controlled. Genetic influence on epigenetic mechanisms and epigenetic influence on genetic expression are potentially important targets for understanding and enhancing stroke recovery.…”

Looking Above but Not Beyond the Genome for Therapeutics in Neurology and Psychiatry: Epigenetic Proteins and RNAs Find a New Focus

“…Selective isoforms responsible for the damaging effects are currently under investigation (Baltan et al, p. XX [25] and Edward Holson et al, p. XX [8]). The role of epigenetic proteins in neural plasticity and stroke rehabilitation is also reviewed, with a particular focus on polycomb proteins, adenosine triphosphate-dependent chromatin modifiers, and the role of HDACs in hippocampal-based plasticity mechanisms (Elder et al, p. XX [26]). …”

Epigenetic changes following traumatic brain injury and their implications for outcome, recovery and therapy

“…Although the field of epigenetics is now well established, interest in the epigenetic mechanisms involved in TBI pathophysiology has only recently gained traction. Indeed, recent reviews in CNS injury support the relevance of epigenetics in this field, but these largely focus on pathophysiology of stroke [28, 30, 76] and spinal cord injury [104]. Moreover, our widening understanding of epigenetic changes associated with neural plasticity, learning and memory (reviewed in [100]) reinforces the prospect that understanding the structural and functional changes that occur following TBI could provide innovative approaches to TBI recovery and rehabilitation.…”