Role of the HSP70 Co-Chaperone SIL1 in Health and Disease.

Cell surface and secreted proteins provide essential functions for multicellular life. They enter the endoplasmic reticulum (ER) lumen co-translationally, where they mature and fold into their complex three-dimensional structures. The ER is populated with a host of molecular chaperones, associated co-factors, and enzymes that assist and stabilize folded states. Together, they ensure that nascent proteins mature properly or, if this process fails, target them for degradation. BiP, the ER HSP70 chaperone, interacts with unfolded client proteins in a nucleotide-dependent manner, which is tightly regulated by eight DnaJ-type proteins and two nucleotide exchange factors (NEFs), SIL1 and GRP170. Loss of SIL1's function is the leading cause of Marinesco-Sjögren syndrome (MSS), an autosomal recessive, multisystem disorder. The development of animal models has provided insights into SIL1's functions and MSS-associated pathologies. This review provides an in-depth update on the current understanding of the molecular mechanisms underlying SIL1's NEF activity and its role in maintaining ER homeostasis and normal physiology. A precise understanding of the underlying molecular mechanisms associated with the loss of SIL1 may allow for the development of new pharmacological approaches to treat MSS.

Cerebellar degeneration and progressive ataxia associated with HIV-virus infection.

INTRODUCTION: The spectrum of neurologic disorders associated with HIV infection is very broad, resulting from direct virus invasion, opportunistic infections, malignancies and toxic effects of drugs. METHODS: Among a large cohort of ataxia patients (N = 1050) evaluated between 2008 and 2017, we detected four patients with HIV-infection who developed a pure progressive cerebellar ataxia syndrome combined with cerebellar atrophy. RESULTS: Adverse drug effects, opportunistic infections and malignancies as well as immune-reconstitution syndrome were ruled out based on history and laboratory data. The exact pathophysiological mechanisms of ataxia in HIV patients is not very clear, but seems to be immune-mediated or a direct neurotoxic virus effect leading to apoptosis of Purkinje and granular cells. CONCLUSION: HIV infection should be investigated in adult patients with undetermined sporadic progressive pure ataxia with cerebellar atrophy.

JC virus granule cell neuronopathy and GCN-IRIS under natalizumab treatment.

Progressive multifocal leukoencephalopathy is the most common clinical presentation of JC virus (JCV)-associated central nervous system (CNS) disease and has emerged as a major safety concern in multiple sclerosis patients treated with the monoclonal antibody natalizumab. Here we report clinical, radiological, and histological findings of a case of cerebellar granule cell neuronopathy (GCN), a JCV-associated CNS disease, so far unreported amongst patients treated with natalizumab. GCN should be considered as a JCV CNS manifestation in patients with newly developed, progressive cerebellar signs under natalizumab treatment, especially in cases where cerebellar atrophy can be visualized by magnetic resonance imaging.

Cerebellar degeneration and hearing loss in a patient with idiopathic myenteric ganglionitis.

A 35-year-old male with an 11-year history of intestinal pseudo-obstruction associated with an idiopathic inflammatory insult of the myenteric plexus and the presence of circulating anti-Hu antibodies developed a neurological syndrome characterized by bilateral hearing loss, deteriorating balance, an unsteady gait and difficulty in estimating distances. A similar neurological syndrome has previously been described in older patients among the paraneoplasic syndromes associated with small-cell lung carcinoma and the presence of circulating anti-Hu antibodies, but never in the rare cancer-free patients with anti-Hu-associated chronic idiopathic intestinal pseudo-obstruction. The patient underwent a steroid treatment. No further episodes of functional intestinal obstruction were observed and, after an initial improvement, the neurological symptoms stabilized, leaving a permanent reduction in hearing function and an unsteady gait. The case shows that an idiopathic inflammatory insult of the myenteric plexus may precede (and perhaps lead to) central nervous system impairment in patients with anti-Hu-associated chronic idiopathic intestinal pseudo-obstruction.

[Cerebellar degeneration associated with anti-Tr antibodies without Hodgkin's disease. Four years follow-up]. / Degeneración cerebelosa con anticuerpos anti-Tr positivos sin linfoma de Hodgkin asociado. Seguimiento durante 4 años.

The presence of antineuronal anti-Tr antibodies is associated to paraneoplastic cerebellar degeneration due to Hodgkin's disease. The anti-Tr can become negative after successful and early treatment of the tumor, and there could even be remission of the cerebellar symptoms in some patients. There are few cases in which no tumor is found when there are anti-Tr. We report the case of a 66 year old man with a severe cerebellar syndrome and anti-Tr in serum detected by immunohistochemistry. After a 4 year follow-up, no underlying tumor has been found. In addition, anti-Tr spontaneously disappeared. The cerebellar degeneration persists and is incapacitating. This case suggests that in a few instances the origin of anti-Tr is not a tumor but another unknown cause. Alternatively the anti-Tr mediated immune response could have eradicated the underlying lymphoma.

Polyglutamine-expanded ataxin-7 promotes non-cell-autonomous purkinje cell degeneration and displays proteolytic cleavage in ataxic transgenic mice.

Spinocerebellar ataxia (SCA) type 7 is an inherited neurodegenerative disorder caused by expansion of a polyglutamine tract within the ataxin-7 protein. To determine the molecular basis of polyglutamine neurotoxicity in this and other related disorders, we produced SCA7 transgenic mice that express ataxin-7 with 24 or 92 glutamines in all neurons of the CNS, except for Purkinje cells. Transgenic mice expressing ataxin-7 with 92 glutamines (92Q) developed a dramatic neurological phenotype presenting as a gait ataxia and culminating in premature death. Despite the absence of expression of polyglutamine-expanded ataxin-7 in Purkinje cells, we documented severe Purkinje cell degeneration in 92Q SCA7 transgenic mice. We also detected an N-terminal truncation fragment of ataxin-7 in transgenic mice and in SCA7 patient material with both anti-ataxin-7 and anti-polyglutamine specific antibodies. The appearance of truncated ataxin-7 in nuclear aggregates correlates with the onset of a disease phenotype in the SCA7 mice, suggesting that nuclear localization and proteolytic cleavage may be important features of SCA7 pathogenesis. The non-cell-autonomous nature of the Purkinje cell degeneration in our SCA7 mouse model indicates that polyglutamine-induced dysfunction in adjacent or connecting cell types contributes to the neurodegeneration.

An autopsy case of ornithine transcarbamylase deficiency.

We present an autopsy case of ornithine transcarbamylase (OTC) deficiency with grumose degeneration in the dentate nucleus of the cerebellum. The patient had intractable neonatal convulsions and hyperammonemia from the 3rd day after birth. Diagnosis of OTC deficiency was made based on null activity of the enzyme and four-base deletions in exon 9 of the OTC gene. Death was due to sepsis as well as disseminated intravascular coagulation at 1 year and 2 months of age. Neuropathology showed multiple cystic changes and ulegyria in the bilateral frontal and parietal lobes. Multiple cysts were associated with the region, which was infiltrated with macrophages surrounded by astroglia showing palisading pattern. Ferrugination was marked in the thalamus and severe neuronal loss with astrogliotic change in the CA1-2 area of the hippocampus. Grumose degeneration was noted in the dentate nucleus of the cerebellum. This is the first report of grumose degeneration in OTC deficiency.

[Hereditary ataxias-overview].

Many of autosomal dominant spinocerebellar ataxias (SCA) are now shown to result from the expansion of unstable trinucleotide repeats. In most SCAs, these repeats are present within coding sequences of the causative genes and translated into polyglutamine tracts. In this overview clinical and molecular genetic features of newly identified group of diseases in this category are briefly summarized. Expanded polyglutamine repeats are supposed to mediate some toxic effects on a certain population of neurons that result in neuronal dysfunction. The current progress in these molecular biological studies on their pathophysiology is also reviewed. In Japan, Friedreich ataxia with intoronic GAA repeat expansions has not been known. Instead, early onset ataxia with Friedreich phenotype, associated with ocular motor apraxia in childhood and with hypoalbuminemia in adult, is the predominant ataxia with Friedreich phenotype, the causative mutation of which was very recently identified.

Serous adenocarcinoma of the uterus presenting as paraneoplastic cerebellar degeneration.

Paraneoplastic cerebellar degeneration is a rare complication of cancer and is most frequently associated with lung, ovary, and breast cancers as well as Hodgkins lymphoma. A 74-year-old female with a past history of breast cancer presented with vomiting, ataxia, slurred speech, and dizziness. Her serum chemistry, thyroid and liver function tests, acetylcholine antibodies, serum cortisol, CT, and MRI imaging were all normal. Serum testing for anti-YO antibodies was positive. Further evaluation including CT of the abdomen and pelvis revealed endometrial thickening. Subsequently, an endometrial biopsy showed a poorly differentiated serous adenocarcinoma. Surgical staging was consistent with a stage IIIc serous adenocarcinoma of the uterus. The risk factors, symptoms, signs, differential diagnosis, and clinical and antibody associations of the paraneoplastic cerebellar degeneration syndrome are reviewed. In addition, an efficient approach to the diagnostic evaluation of such patients is proposed.

[Autoantibody to glutamate decarboxylase in a patient with spinocerebellar degeneration and Sjögren syndrome].

We report a 52-year-old woman with Sjögren syndrome from the age of 46, developed cerebellar ataxia, autonomic dysfunction and dysarthria at 50. She had no family history, and all known causes of cerebellar disease were excluded. Serum of the patient contained autoantibodies directed against glutamic acid decarboxylase (GAD) which was an enzyme involved in the biosynthesis of GABA. She also had autoantibodies that were specific with Sjögren syndrome (SS-A, anti-nuclear antibody). Anti-GAD antibody changed into negative after high dose intravenous and oral corticosteroid therapy, but symptoms did not improve. Western blot method revealed abnormal bands to human neuroblastoma cell line (10, 43, 49 kDa), considered relatively specific to nervous tissue. In this case cerebellar ataxia and atrophy were caused by autoimmune pathogenesis including cerebellar GABAergic system and central nerve cells.

The pathophysiology of paraneoplastic neurological syndromes.

Paraneoplastic neurological diseases are a group of neurological disorders associated with neoplastic tumors but not due to tumoral extension, metabolic, infectious, vascular or toxic complications of these tumors or their treatment. In the majority of paraneoplastic neurological disorders, circulating autoantibodies directed against neurons have been found in the serum and/or the CSF suggesting, and in some cases implicating, autoimmunity in the pathophysiology of these diseases. The finding of autoimmune phenomena during the course of paraneoplastic neurological disorders is of importance: from a practical point of view, since the detection of anti-neuronal autoantibodies is of great diagnostic help and should lead to the thorough search of the associated tumor often at an early stage of its development; from a theoretical point of view, these disorders represent a peculiar type of molecular mimicry. Tumoral neontigens having structural homology or identity with neuronal autoantigens elicit autoreactivity. The immunological effector mechanisms involved in the pathophysiology of paraneoplastic syndromes appear to differ according to the disease: autoantibodies are pathogenic in Lambert-Eaton syndrome whereas, in paraneoplastic cerebellar degeneration and in the Hu syndrome, the cellular immune response might play a greater role.

CNS sequelae in Langerhans cell histiocytosis: progressive spinocerebellar degeneration as a late manifestation of the disease.

Central nervous system involvement in Langerhans cell histiocytosis (LCH), formerly known as histiocytosis X, is manifested mainly by diabetes insipidus reflecting local infiltration of Langerhans cells into the posterior pituitary or hypothalamus. We describe two patients with progressive spinocerebellar degeneration appearing 4 and 6 years after the initial diagnosis of LCH. No correlation was found between the clinical course of the disease or its treatment and the neurological impairment. An extensive search for metabolic, toxic, neoplastic, and hereditary etiologies for progressive cerebellar degeneration was negative.

[Endocrinologic and metabolic complications of Alagille syndrome]. / Endokrinologische und metabolische Komplikationen des Alagille-Syndroms.

BACKGROUND: Patients with gastrointestinal and hepatobiliary disorders, either congenital or acquired early in childhood, are at high risk for various endocrine and metabolic abnormalities. CASE REPORT: A 27-year-old woman with Alagille's syndrome presented with progressive jaundice and gait disturbances following surgery and ingestion of oral contraceptives. On physical examination, short stature, facial dysmorphism and neuromuscular symptoms such as polyneuropathy and spinocerebellar ataxia were noted. Serum concentrations of total bilirubin (54 mg/dl) and alkaline phosphatase were markedly increased, whereas serum levels of haptoglobin, zinc, vitamin D and E were decreased. Although prehepatic or intrahepatic etiologies of jaundice were more likely in this patient, posthepatic etiologies were ruled out by abdominal ultrasound and endoscopic retrograde cholangio-pancreaticography. Based on a working diagnosis of acute drug-induced cholestasis, treatment with high doses of lipid-soluble vitamins and ursodeoxycholic acid was initiated. In response to therapy, her abnormal laboratory results normalized and her neurologic symptoms markedly improved. CONCLUSION: This clinicopathological conference of a patient with Alagille's syndrome illustrates the clinical presentation and therapy of metabolic and endocrine complications in chronic cholestasis.

Ataxin-1 with an expanded glutamine tract alters nuclear matrix-associated structures.

Spinocerebellar ataxia type 1 (SCA1) is one of several neurodegenerative disorders caused by an expansion of a polyglutamine tract. It is characterized by ataxia, progressive motor deterioration, and loss of cerebellar Purkinje cells. To understand the pathogenesis of SCA1, we examined the subcellular localization of wild-type human ataxin-1 (the protein encoded by the SCA1 gene) and mutant ataxin-1 in the Purkinje cells of transgenic mice. We found that ataxin-1 localizes to the nuclei of cerebellar Purkinje cells. Normal ataxin-1 localizes to several nuclear structures approximately 0.5 microm across, whereas the expanded ataxin-1 localizes to a single approximately 2-microm structure, before the onset of ataxia. Mutant ataxin-1 localizes to a single nuclear structure in affected neurons of SCA1 patients. Similarly, COS-1 cells transfected with wild-type or mutant ataxin-1 show a similar pattern of nuclear localization; with expanded ataxin-1 occurring in larger structures that are fewer in number than those of normal ataxin-1. Colocalization studies show that mutant ataxin-1 causes a specific redistribution of the nuclear matrix-associated domain containing promyelocytic leukaemia protein. Nuclear matrix preparations demonstrate that ataxin-1 associates with the nuclear matrix in Purkinje and COS cells. We therefore propose that a critical aspect of SCA1 pathogenesis involves the disruption of a nuclear matrix-associated domain.

[Small-cell carcinoma of the lung with paraneoplastic cerebellar degeneration].

A 50-year-old man was admitted to our hospital because of slowly progressing ataxia. After the neurological examination and after observation of the clinical course, paraneoplastic cerebellar degeneration was suspected. Extensive examination revealed a malignant tumor in the right upper lobe of the lung. Immunoblotting with rat cerebellum revealed a 68 KDa protein in the patient's serum, which suggested that paraneoplastic cerebellar degeneration was caused by an auto-antibody. Anti-cancer drugs and radiation therapy were begun 4 months after the onset of symptoms. After 4 months of therapy, the lung cancer had shrunk, but the neurological symptoms had become more severe.