Abstract
The homeostasis of protein palmitoylation and depalmitoylation is essential for proper physiological functions in various tissues, in particular the central nervous system (CNS). The dysfunction of PPT1 (PPT1-KI, infantile neuronal ceroid lipofuscinosis [INCL] mouse model), which catalyze the depalmitoylation process, results in serious neurodegeneration accompanied by severe astrogliosis in the brain. Endeavoring to determine critical factors that might account for the pathogenesis in CNS by palm-proteomics, glial fibrillary acidic protein (GFAP) was spotted, indicating that GFAP is probably palmitoylated. Questions concerning if GFAP is indeed palmitoylated in vivo and how palmitoylation of GFAP might participate in neural pathology remain unexplored and are waiting to be investigated. Here we show that GFAP is readily palmitoylated in vitro and in vivo; specifically, cysteine-291 is the unique palmitoylated residue in GFAP. Interestingly, it was found that palmitoylated GFAP promotes astrocyte proliferation in vitro. Furthermore, we showed that PPT1 depalmitoylates GFAP, and the level of palmitoylated GFAP is overwhelmingly up-regulated in PPT1-knockin mice, which lead us to speculate that the elevated level of palmitoylated GFAP might accelerate astrocyte proliferation in vivo and ultimately led to astrogliosis in INCL. Indeed, blocking palmitoylation by mutating cysteine-291 into alanine in GFAP attenuate astrogliosis, and remarkably, the concurrent neurodegenerative pathology in PPT1-knockin mice. Together, these findings demonstrate that hyperpalmitoylated GFAP plays critical roles in regulating the pathogenesis of astrogliosis and neurodegeneration in the CNS, and most importantly, pinpointing that cysteine-291 in GFAP might be a valuable pharmaceutical target for treating INCL and other potential neurodegenerative diseases.
Highlights
S-palmitoylation can reversibly modify candidate proteins by adding a 16-carbon saturated fatty acid on cysteine residues through thioester linkage [1, 2]
Pursuing the questions respecting whether Glial fibrillary acidic protein (GFAP) is truly palmitoylated in vivo and how palmitoylation might affect the physiological roles of GFAP led us to uncover a pathological mechanism that hyperpalmitoylated GFAP promotes astrogliosis, and blocking of which alleviate astrogliosis and neurodegenerative pathology in infantile neuronal ceroid lipofuscinosis (INCL) mouse model
We demonstrate that GFAP palmitoylation is regulated by PPT1, a palmitoylprotein thioesterase linked to a childhood neurodegenerative disorder, infantile neuronal ceroid lipofuscinosis
Summary
S-palmitoylation can reversibly modify candidate proteins by adding a 16-carbon saturated fatty acid (palmitic acid) on cysteine residues through thioester linkage [1, 2]. The disruption of such cycling can cause severe physiological consequences; for example, a common natural mutation in ppt (c.451C > T) results in the dysfunction of PPT1 and an early form of neurodegenerative disease infantile neuronal ceroid lipofuscinosis (INCL). One of the typical phenomena in this disease is the gradual loss of neurons associated with increasingly expanded astrogliosis (the activation of astrocytes) in PPT1-KI mice, as displayed by seizure and shortened longevity in physiological level at later stage of life (6 to 8 mo). We demonstrate that GFAP palmitoylation is regulated by PPT1, a palmitoylprotein thioesterase linked to a childhood neurodegenerative disorder, infantile neuronal ceroid lipofuscinosis. We conclude that accumulation of palmitoylated GFAP contributes to the pathogenesis of astrogliosis and neurodegeneration, suggesting that targeting the modified cysteine in GFAP may be a potential therapeutic strategy for the treatment of infantile neuronal ceroid lipofuscinosis and other neurodegenerative disorders
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