Neuroinflammation and progressive myoclonus epilepsies: from basic science to therapeutic opportunities

Abstract

Progressive myoclonus epilepsies (PMEs) are a group of genetic neurological disorders characterised by the occurrence of epileptic seizures, myoclonus and progressive neurological deterioration including cerebellar involvement and dementia. The primary cause of PMEs is variable and alterations in the corresponding mutated genes determine the progression and severity of the disease. In most cases, they lead to the death of the patient after a period of prolonged disability. PMEs also share poor information on the pathophysiological bases and the lack of a specific treatment. Recent reports suggest that neuroinflammation is a common trait under all these conditions. Here, we review similarities and differences in neuroinflammatory response in several PMEs and discuss the window of opportunity of using anti-inflammatory drugs in the treatment of several of these conditions.

Canine Lafora Disease: An Unstable Repeat Expansion Disorder

“…In a mouse model of the diseases, this progressive increase in inflammatory response correlates with age, providing a possible explanation for the worsening of the pathophysiological clinical signs over time [ 31 ]. Improved understanding of the pathophysiology of Lafora’s disease has sparked the possibility of new treatment strategies, as reviewed by Sanz and Serratosa [ 33 ]. Interestingly for both humans and dogs, the first clinical signs of Lafora disease occur at a similar chronological age (in dogs at seven years of age and in humans during late childhood/early adolescence).…”

TargetingGys1with AAV‐SaCas9 decreases pathogenic polyglucosan bodies and neuroinflammation in Adult Polyglucosan Body and Lafora disease mouse models

“…The recent recognition of the inflammatory component in the pathogenesis of LD opened novel anti-inflammatory therapeutic possibilities, which are presently being studied, while more permanent root cause-based therapies are developed [14][15][16]51]. A side result of our study is the identification of similar transcription-level immune abnormalities, and their correction, in APBD.…”

“…Transcriptomic analyses showed that 94% of genes upregulated in the disease encode proteins of inflammatory and immune system pathways [14]. Finally, downregulation of GYS1 activity by transgenic or other means resulting in PB reductions partially corrected these abnormalities [15–20]. Of the several hundred immune system genes shown to be dysregulated in the transcriptomic studies, a subset (less than 10) was tested and confirmed by qRT-PCR, of which several were shown to already be overexpressed at earlier stages of the disease [14, 20].…”

Glial Contributions to Lafora Disease: A Systematic Review

“…One is the accumulation of glycogen in astrocytes, given that these processes depend on glycogenolysis [ 38 , 40 , 69 , 94 , 95 ]. Second, inflammatory cytokines (e.g., TNFα and IL-6) released by proinflammatory glial cells reduce glutamate uptake by EAAT2 transporters and promote its astrocytic release [ 96 , 97 , 98 ]. A third mechanism demonstrated in cellular [ 52 ] and mouse models [ 53 ] of LD is the functional reduction in the astrocytic EEAT2 transporter [ 52 , 53 ] linked to its altered ubiquitination and recycling due to the deficiency of the laforin/malin complex [ 54 ].…”