Disruption of Tmem30a results in cerebellar ataxia and degeneration of Purkinje cells

Yang, Yeming; Sun, Kuanxiang; Liu, Wenjing; Zhang, Lin; Peng, Kun; Zhang, Shanshan; Li, Shujin; Mu, Yang; Jiang, Zhilin; Lu, Fang; Zhu, Xuejun

doi:10.1038/s41419-018-0938-6

Cited by 26 publications

(33 citation statements)

References 54 publications

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“…4 b). We also evaluated whether ataxia-like motor impairment induced by neuroinflammation was associated with the loss of Purkinje cells, a typical neuropathologic feature of CAs 15 . Relative to control mice, LPS-injected mice exhibited > 50% reduction in calbindin protein, which indicates Purkinje cell death, in the cerebellum 7 days after LPS injection (Fig.…”

Section: Resultsmentioning

confidence: 99%

Lipopolysaccharide administration for a mouse model of cerebellar ataxia with neuroinflammation

Hong

Yoon

Nam

et al. 2020

Sci Rep

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Most cerebellar ataxias (cAs) are incurable neurological disorders, resulting in a lack of voluntary control by inflamed or damaged cerebellum. Although CA can be either directly or indirectly related to cerebellar inflammation, there is no suitable animal model of CA with neuroinflammation. In this study, we evaluated the utility of an intracerebellar injection of lipopolysaccharide (LpS) to generate an animal model of inflammatory CA. We observed that LPS administration induced the expression of pro-inflammatory molecules following activation of glial cells. In addition, the administration of LPS resulted in apoptotic purkinje cell death and induced abnormal locomotor activities, such as impaired motor coordination and abnormal hindlimb clasping posture. Our results suggest that intracerebellar LPS administration in experimental animals may be useful for studying the inflammatory component of CA. Cerebellar ataxias (CAs) are motor neuron diseases caused by pathological processes affecting the cerebellum or its associated pathways 1,2. They are characterised by symptoms such as abnormal coordination of balance, movement and gait. Currently, most CAs are incurable, with few exceptions, and only symptom alleviation is possible 3. CAs can be caused by genetic defects, sporadic neurodegenerative disorders, and acquired conditions (for example, infections, toxic reactions, alcohol, and vitamin deficiencies), but they can also arise for unknown reasons 1,3,4. In particular, many reports have shown a close relationship between cerebellar inflammation and CA 1,3,5. The activation of glial cells resulting in the production of pro-inflammatory molecules has been observed in many animal models of CA and is also evident in the cerebellums of patients with CA 6-9. Furthermore, cerebellar inflammation has been shown to induce the loss of Purkinje cells, which results in cerebellar dysfunction 1,7. Although the understanding of CA pathogenesis associated with genetic causes, cerebellar neurotoxicity, and physical damage has contributed to the development of some animal models of CA 1,3 , there is no suitable animal model to study CA following glial activation and neurotoxic cerebellar inflammation in vivo. Neuroinflammation plays a crucial role in the pathogenesis and progression of neurodegenerative disorders such as Parkinson's disease and Alzheimer's disease 10. As a potent stimulator of neuroinflammation, lipopolysaccharide (LPS) has been used to mediate neurodegenerative progression 11. An accumulation of evidence has shown that LPS-induced neuroinflammation causes neuronal damage through activation of microglia and astrocytes, M1 microglial polarization and the release of pro-inflammatory mediators. For example, LPS injected into the substantia nigra induces microglia activation, which causes the degeneration of dopamine neurons that constitutes the pathological basis of Parkinson's disease 12. In addition, LPS causes an increase in amyloid beta, which results in demyelination and oligodendrocyte injury in mice brains, w...

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Section: Resultsmentioning

confidence: 99%

Lipopolysaccharide administration for a mouse model of cerebellar ataxia with neuroinflammation

Hong

Yoon

Nam

et al. 2020

Sci Rep

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“…Increased expression of the glial fibrillary acidic protein (GFAP), astrogliosis, and thickening of BG processes were also observed in regions with extensive PC loss in a PC-specific Tmem30a KO mouse model that displays early-onset ataxia. In this case, astrocytic reactivity resulted from neuronal impairments and/or degeneration and likely further exacerbated neuronal loss contributing to disease progression, as will be discussed later [48]. A prominent astroglial activation and an impaired functioning of the glutamate-aspartate transporter GLAST, mediated by the proinflammatory cytokine interleukin-1β (IL-1β), were observed in the cerebella of experimental autoimmune encephalomyelitis (EAE) mice.…”

Section: Astrocytes Impairments Are Often Associated To Ataxic-like Smentioning

confidence: 97%

Cerebellar Astrocytes: Much More Than Passive Bystanders In Ataxia Pathophysiology

Cerrato

2020

JCM

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Ataxia is a neurodegenerative syndrome, which can emerge as a major element of a disease or represent a symptom of more complex multisystemic disorders. It comprises several forms with a highly variegated etiology, mainly united by motor, balance, and speech impairments and, at the tissue level, by cerebellar atrophy and Purkinje cells degeneration. For this reason, the contribution of astrocytes to this disease has been largely overlooked in the past. Nevertheless, in the last few decades, growing evidences are pointing to cerebellar astrocytes as crucial players not only in the progression but also in the onset of distinct forms of ataxia. Although the current knowledge on this topic is very fragmentary and ataxia type-specific, the present review will attempt to provide a comprehensive view of astrocytes’ involvement across the distinct forms of this pathology. Here, it will be highlighted how, through consecutive stage-specific mechanisms, astrocytes can lead to non-cell autonomous neurodegeneration and, consequently, to the behavioral impairments typical of this disease. In light of that, treating astrocytes to heal neurons will be discussed as a potential complementary therapeutic approach for ataxic patients, a crucial point provided the absence of conclusive treatments for this disease.

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“…We reported a conditional knockout (cKO) of Tmem30a in the cerebellum with ataxia phenotype using Pcp2‐Cre(Yang et al . ). Since Pcp2‐Cre is also expressed in the rod bipolar cells, we studied rod bipolar cells in this mouse model to elucidate the function of Tmem30a in RBCs.…”

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confidence: 97%

Tmem30a deficiency leads to retinal rod bipolar cell degeneration

Yang

Liu

Sun

et al. 2019

Journal of Neurochemistry

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Phospholipids are asymmetrically distributed across the mammalian plasma membrane, with phosphatidylserine (PS) and phosphatidylethanolamine concentrated in the cytoplasmic leaflet of the membrane bilayer and phosphatidylcholine in the exoplasmic leaflet. This asymmetric distribution is dependent on a group of P4 ATPases called PS flippases. The proper transport and function of PS flippases require a β‐subunit transmembrane protein 30A (TMEM30A). Disruption of PS flippases leads to several human diseases. Tmem30a is essential for photoreceptor survival. However, the roles of Tmem30a in the retinal rod bipolar cells (RBC) remain elusive. To investigate the role of Tmem30a in the RBCs, we generated a RBC‐specific Tmem30a knockout (cKO) mouse model using PCP2‐Cre line. The Tmem30a cKO mice exhibited defect in RBC function and progressive RBC death. PKCα staining of retinal cryosections from cKO mice revealed a remarkable dendritic sprouting of rod bipolar cells during the early degenerative process. Immunostaining analysis of PSD95 and mGluT6 expression demonstrated that rod bipolar cells in Tmem30a cKO retinas exhibited aberrant dendritic sprouting as a result of impaired synaptic efficacy, which implied a crucial role for Tmem30a in synaptic transmission in the retina. In addition, loss of Tmem30a led to reactive gliosis with increased expression of glial fibrillary acidic protein and CD68. TUNEL staining suggested that apoptotic cell death occurred in the retinal inner nuclear layer (INL). Our data show that loss of Tmem30a in RBCs results in dendritic sprouting of rod bipolar cells, increased astrogliosis and RBC death. Taken together, our studies demonstrate an essential role for Tmem30a in the retinal bipolar cells. Cover Image for this issue: doi: .

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Disruption of Tmem30a results in cerebellar ataxia and degeneration of Purkinje cells

Cited by 26 publications

References 54 publications

Lipopolysaccharide administration for a mouse model of cerebellar ataxia with neuroinflammation

Lipopolysaccharide administration for a mouse model of cerebellar ataxia with neuroinflammation

Cerebellar Astrocytes: Much More Than Passive Bystanders In Ataxia Pathophysiology

Tmem30a deficiency leads to retinal rod bipolar cell degeneration

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