White matter injury across neurodegenerative disease

Abstract

Oligodendrocytes (OLs), the myelin-generating cells of the central nervous system (CNS), are active players in shaping neuronal circuitry and function. It has become increasingly apparent that injury to cells within the OL lineage plays a central role in neurodegeneration. In this review, we focus primarily on three degenerative disorders in which white matter loss is well documented: Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS). We discuss clinical data implicating white matter injury as a key feature of these disorders, as well as shared and divergent phenotypes between them. We examine the cellular and molecular mechanisms underlying the alterations to OLs, including chronic neuroinflammation, aggregation of proteins, lipid dysregulation, and organellar stress. Last, we highlight prospects for therapeutic intervention targeting the OL lineage to restore function.

Keywords: Alzheimer’s disease; Parkinson’s disease; amyotrophic lateral sclerosis; lipid dysregulation; neuroinflammation; organellar stress.

Figure 1.. Neuroinflammation by the innate and adaptive immune systems induces oligodendrocyte injury.

The infiltration of activated peripheral immune cells, in particular T cells, has been observed in chronic neurodegenerative conditions, including AD, PD, and ALS. These cells can recognize specific antigens within the CNS, as well as produce inflammatory cytokines that are known to disrupt OPC differentiation. The resident cells of the CNS, microglia and astrocytes, also contribute to the inflammatory milieu through the increased secretion of proinflammatory cytokines and chemokines that directly inhibit OPC maturation in mature, myelinating oligodendrocytes. Additionally, microglia can adopt a specific phenotype to phagocytose damaged myelin; however, this can impair their ability to clear amyloid plaques and perpetuate damage via aggregated proteins as outlined in Figure 2. Abbreviations: Aβ, amyloid beta; OPC, oligodendrocyte precursor cell. Figure created with BioRender.com.

Figure 2.. Misfolded proteins and protein aggregates impair homeostatic OPC and oligodendrocyte functions.

AD, PD, and ALS are characterized by the presence of protein aggregates and misfolded proteins. A) In AD and PD, protein aggregates (amyloid-β plaques and αsynuclein) can directly impair OPC maturation and induce alternative phenotypes within OPCs, including antigen presentation and senescence. The appearance of these phenotypes also prevents the ability of OPCs to differentiate into OLs, though the mechanisms underlying this observation are not known. Additionally, in response to cortical amyloid deposition, oligodendrocytes upregulated genes associated with β-amyloid production, suggesting they may be an unlikely source of amyloid plaques [37]. B) Accumulation of mutant SOD1 or TDP43 in ALS decreases the oligodendrocyte-specific lactate transporter, MCT1, and impairs axonal energy metabolism [62,64]. Aggregation of myelin proteins, specifically MBP, have been identified and this was associated with an increase in citrullination, a post-translational modification that inhibits the ability of MBP to bind the plasma membrane [63]. Abbreviations: AD, Alzheimer’s disease; ALS, amyotrophic lateral sclerosis; MCT1, monocarboxylate transporter 1; mtSOD1, mutant superoxide dismutase 1; PM, plasma membrane. Figure created with BioRender.com.

Figure 3.. Organellar dysfunction and lipid dysregulation are critical mediators of oligodendrocyte injury in neurodegeneration.

Depletion of myelin-specific lipids has been observed across neurodegenerative conditions, including in response to amyloid plaques and the major dementia risk allele TMEM106B. Organellar stress also occurs downstream of neuroinflammation and aggregated proteins. Increased expression of the master lysosomal biogenesis transcription factor, TFEB, is observed in post-mortem tissue from patients with TREM2 risk-modifying alleles; TFEB has been shown to coordinate oligodendrocyte cell death during development and represses myelination. Endoplasmic reticulum stress, which halts global translation and leads to the selective transcription of stress-related genes via ATF4 translocation, is associated with cholesterol accumulation in APOE4 carriers. Failure to resolve chronic ER stress becomes deleterious over time, and is characterized by persistent upregulation of GADD34. Overactivation of Drp1 on mitochondria activates the NLRP3 inflammasome and activates pyroptotic cell death and myelin loss. Loss of glycolytic and ketolytic pathway genes within oligodendrocytes has also been observed in Alzheimer’s disease post-mortem tissue. Abbreviations: Atf4; activating transcription factor 4; Drp1, dynamin-related protein 1; eIF2α, eukaryotic transcription factor 2 alpha; ER, endoplasmic reticulum; GADD34, growth arrest and DNA damage-inducible protein 34; MPTP, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine; TFEB, transcription factor EB; TMEM106B, transmembrane protein 106B. Figure created with BioRender.com.