Pushing Forward: Remyelination as the New Frontier in CNS Diseases

In light of the current clinical success of immunomodulatory treatments in multiple sclerosis, the development of neuro- and glioprotective treatment options has received increased attention. Several other neurological diseases are also characterized by loss of oligodendrocytes and myelin damage. Myelin sheaths are generated by oligodendrocytes and represent key structures for saltatory signal propagation and trophic support of axons. Remyelination, as one of the few spontaneous repair processes in the CNS, can provide a certain degree of myelin reconstitution but remains overall inefficient. Migration, survival, proliferation, and differentiation have been recognized as key processes for successful myelin regeneration by resident oligodendroglial precursor cells. Recently, multiple pharmacological compounds have emerged that exert beneficial effects on oligodendroglial precursor cells, thus representing potential candidates for the development of future myelin repair therapies. The evolutionary acquisition of myelin sheaths around large caliber axons in the central nervous system (CNS) represented a milestone in the development of vertebrate higher brain function. Myelin ensheathment of axons enabled saltatory conduction and thus accelerated information processing. However, a number of CNS diseases harm or destroy myelin and oligodendrocytes (myelin-producing cells), ultimately resulting in demyelination. In the adult CNS, new oligodendrocytes can be generated from a quiescent pool of precursor cells, which – upon differentiation – can replace lost myelin sheaths. The efficiency of this spontaneous regeneration is limited, which leads to incomplete remyelination and residual clinical symptoms. Here, we discuss CNS pathologies characterized by white matter degeneration and regeneration and highlight drugs that could potentially serve as remyelination therapies. The evolutionary acquisition of myelin sheaths around large caliber axons in the central nervous system (CNS) represented a milestone in the development of vertebrate higher brain function. Myelin ensheathment of axons enabled saltatory conduction and thus accelerated information processing. However, a number of CNS diseases harm or destroy myelin and oligodendrocytes (myelin-producing cells), ultimately resulting in demyelination. In the adult CNS, new oligodendrocytes can be generated from a quiescent pool of precursor cells, which – upon differentiation – can replace lost myelin sheaths. The efficiency of this spontaneous regeneration is limited, which leads to incomplete remyelination and residual clinical symptoms. Here, we discuss CNS pathologies characterized by white matter degeneration and regeneration and highlight drugs that could potentially serve as remyelination therapies. is the most common form of dementia. AD has predominantly been associated with neuronal death due to the accumulation of extracellular β-amyloid (Aβ) plaques and intracellular tau-protein neurofibrillary tangles [135Kumar A. et al.A review on Alzheimer's disease pathophysiology and its management: an update.Pharmacol. Rep. 2015; 67: 195-203Crossref PubMed Scopus (188) Google Scholar]. Prior to the appearance of typical Aβ plaques and tangles, myelin abnormalities occur in the AD brain and Aβ itself was reported to lead to increased oligodendroglial apoptosis [41Desai M.K. et al.Triple-transgenic Alzheimer's disease mice exhibit region-specific abnormalities in brain myelination patterns prior to appearance of amyloid and tau pathology.Glia. 2009; 57: 54-65Crossref PubMed Scopus (78) Google Scholar, 42Roth A.D. et al.Oligodendrocytes damage in Alzheimer's disease: beta amyloid toxicity and inflammation.Biol. Res. 2005; 38: 381-387Crossref PubMed Google Scholar]. In addition, myelin breakdown releases toxic iron promoting Aβ formation [44Bartzokis G. et al.Human brain myelination and amyloid beta deposition in Alzheimer's disease.Alzheim. Dement. 2007; 3: 122-125Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar]. this neurodegenerative disease features progressive loss of bulbar and limb functions due to the degeneration of both upper and lower motor neurons [136Kuhnlein P. et al.Diagnosis and treatment of bulbar symptoms in amyotrophic lateral sclerosis.Nat. Clin. Pract. Neurol. 2008; 4: 366-374Crossref PubMed Scopus (85) Google Scholar]. The underlying cause for neurodegeneration is still largely unknown but several lines of evidence point to the importance of oxidative stress [137Barber S.C. Shaw P.J. Oxidative stress in ALS: key role in motor neuron injury and therapeutic target.Free Radic. Biol. Med. 2010; 48: 629-641Crossref PubMed Scopus (260) Google Scholar]. Particularly, the so-called Cu–Zn superoxide dismutase (SOD1) has been the focus of attention with approximately 20% of familial ALS cases being associated with mutations in this gene [138Ivanova M.I. et al.Aggregation-triggering segments of SOD1 fibril formation support a common pathway for familial and sporadic ALS.Proc. Natl. Acad. Sci. U.S.A. 2014; 111: 197-201Crossref PubMed Scopus (0) Google Scholar]. In early ALS, OPCs proliferate but seem to be blocked in their capacity to mature [38Kang S.H. et al.Degeneration and impaired regeneration of gray matter oligodendrocytes in amyotrophic lateral sclerosis.Nat. Neurosci. 2013; 16: 571-579Crossref PubMed Scopus (168) Google Scholar]. In general, expression of lactate transporters is decreased in ALS brains affecting energy supply for neurons and oligodendrocytes themselves [29Lee Y. et al.Oligodendroglia metabolically support axons and contribute to neurodegeneration.Nature. 2012; 487: 443-448Crossref PubMed Scopus (480) Google Scholar], which might explain why spinal cord mature oligodendrocytes degenerate in ALS even prior to the development of clinical symptoms. or stroke is the most common acute CNS disease and a major cause of mortality and morbidity throughout the world [139Prabhakaran S. et al.Acute stroke intervention: a systematic review.JAMA. 2015; 313: 1451-1462Crossref PubMed Scopus (127) Google Scholar]. Besides hypoxic neuronal death as a result of disrupted cerebral blood flow, myelin loss seems to play a decisive role in the long-term clinical outcome [140Zhou J. et al.Long-term post-stroke changes include myelin loss, specific deficits in sensory and motor behaviors and complex cognitive impairment detected using active place avoidance.PLoS ONE. 2013; 8: e57503Crossref PubMed Scopus (0) Google Scholar]. Oligodendrocytes are highly sensitive to ischemic injury due to their high lipid content (myelin sheaths) and high iron content (as pointed out earlier in the context of AD). Resident OPCs in ischemia suffer from oxidative stress leading to substantial cell death and mature oligodendrocytes are harmed by glutamate-mediated excitotoxicity [57Matute C. et al.Excitotoxic damage to white matter.J. Anat. 2007; 210: 693-702Crossref PubMed Scopus (0) Google Scholar]. Increasing OPC numbers initiating differentiation were observed in the ischemic penumbra of rats [58Ohta K. et al.Dissociative increase of oligodendrocyte progenitor cells between young and aged rats after transient cerebral ischemia.Neurosci. Lett. 2003; 335: 159-162Crossref PubMed Scopus (0) Google Scholar] so that exogenous stimulation of myelin repair could potentially contribute to recovery from ischemia. Specific blockade of proton-gated Ca2+-permeable transient receptor potential (TRP) channels could be an alternative therapeutic approach as they were recently shown to damage myelin in white matter ischemia [141Hamilton N.B. et al.Proton-gated Ca-permeable TRP channels damage myelin in conditions mimicking ischaemia.Nature. 2016; 529: 523-527Crossref PubMed Google Scholar]. based on the clinical disease course, different subtypes of MS can be distinguished [142Polman C.H. et al.Diagnostic criteria for multiple sclerosis: 2010 revisions to the McDonald criteria.Ann. Neurol. 2011; 69: 292-302Crossref PubMed Scopus (3363) Google Scholar]. Relapsing remitting MS (RRMS), the most common type (80–90% of patients), is characterized by acute disease exacerbations featuring demyelination followed by total or partial recovery of previously worsened functions. RRMS may transform into secondary progressive MS (SPMS), a disease form with or without eventual relapses and minor remissions that ultimately occurs in approximately 40% of all relapsing remitting courses. Thirdly, primary progressive MS (PPMS; approximately 15% of all patients) shows a steady worsening of symptoms without relapses or remissions and is most common among patients with a late disease onset. In both progressive disease forms, neurodegeneration outweighs inflammatory activity and damage steadily accumulates, whereas during early disease stages demyelinated lesions can regenerate that translates to transient functional improvement and clinical remission. Regeneration and remyelination in all MS types depend on the recruitment of resident OPCs that can replace lost oligodendrocytes. The remyelination process is tightly regulated by numerous extrinsic and intrinsic factors and its efficiency is overall low, decreasing further as the disease progresses. is one of the most intriguing CNS diseases characterized by oligodendroglial cell death – a neurodegenerative disorder featuring myelin and axonal loss and subsequent gliosis [35Ahmed Z. et al.Identification and quantification of oligodendrocyte precursor cells in multiple system atrophy, progressive supranuclear palsy and Parkinson's disease.Brain Pathol. 2013; 23: 263-273Crossref PubMed Scopus (0) Google Scholar]. Clinically, MSA occurs in different subtypes including a parkinsonian type (MSA-P) presenting with rigidity, bradykinesia, tremor, and postural instability and a cerebellar type (MSA-C) in which ataxia and dysarthria predominate. Accumulation of misfolded α-synuclein in MSA occurs predominantly in oligodendrocytes and myelin basic protein (MBP) metabolism was found to be dysregulated even prior to synuclein deposition. There is evidence that oligodendrocytes actively participate in the disease process by transferring toxic α-synuclein to neurons leading to cell death (see also [31Jellinger K.A. Neuropathology of multiple system atrophy: new thoughts about pathogenesis.Mov. Disord. 2014; 29: 1720-1741Crossref PubMed Scopus (36) Google Scholar] for an overview on this disease). In addition, extracellular as well as endogenously produced α-synuclein inhibits glial differentiation resulting in elevated numbers of immature OPCs in MSA brain tissue [34Ettle B. et al.Intracellular alpha-synuclein affects early maturation of primary oligodendrocyte progenitor cells.Mol. Cell. Neurosci. 2014; 62: 68-78Crossref PubMed Scopus (0) Google Scholar, 36May V.E. et al.alpha-Synuclein impairs oligodendrocyte progenitor maturation in multiple system atrophy.Neurobiol. Aging. 2014; 35: 2357-2368Abstract Full Text Full Text PDF PubMed Scopus (16) Google Scholar]. a psychiatric disorder of largely unknown etiology manifesting itself with so-called ‘positive’ symptoms such as delusions, hallucinations, thought disorganization, and ‘negative’ symptoms such as depression and social withdrawal [143Andreasen N.C. Symptoms, signs, and diagnosis of schizophrenia.Lancet. 1995; 346: 477-481Abstract PubMed Scopus (0) Google Scholar]. Myelin-forming oligodendrocytes are currently thought to contribute to psychiatric diseases in many ways, via hypomyelination, hypermyelination, as well as metabolic support [144Nave K.A. Ehrenreich H. Myelination and oligodendrocyte functions in psychiatric diseases.JAMA Psychiatry. 2014; 71: 582-584Crossref PubMed Scopus (0) Google Scholar]. In the SZ brain, key oligodendroglial and myelination genes are downregulated and white matter changes indicating disturbed myelin maturation can be detected [47Tkachev D. et al.Oligodendrocyte dysfunction in schizophrenia and bipolar disorder.Lancet. 2003; 362: 798-805Abstract Full Text Full Text PDF PubMed Scopus (645) Google Scholar]. Disrupted-in-schizophrenia-1 (DISC1), one of the most relevant genes for the development of SZ, was shown to inhibit oligodendroglial differentiation [49Hattori T. et al.DISC1 (disrupted-in-schizophrenia-1) regulates differentiation of oligodendrocytes.PLoS ONE. 2014; 9: e88506Crossref PubMed Scopus (0) Google Scholar].