The Neuronal Ceroid-Lipofuscinoses. Recent Advances

The neuronal ceroid lipofuscinoses (NCLs) represent a group of neurodegenerative disorders characterised by progressive visual failure, neurodegeneration, epilepsy and the accumulation of an autofluorescent lipopigment in neurons and other cells. The main childhood subtypes are infantile (INCL; CLN1 ), classical late infantile (LINCL; CLN2 ) and juvenile NCL (J NCL; CLN3 ), distinguished on the basis of age of onset, clinical course and ultrastructural morphology, and recently genetic analysis. In addition several variant forms of the disease complex have been described as well as a rare adult onset form. Advances in both genetics and biochemistry have led to the identification of the genes for the three main subtypes of childhood NCL and their corresponding protein products and to mapping of two additional genes for two variant forms. The disease causing genes in both INCL and classical LINCL have been shown to encode lysosomal enzymes whilst the JNCL gene codes for a protein whose function is as yet unknown.     

Investigation of Batten Disease with the YeastSaccharomyces cerevisiae

TheCLN3gene, which encodes the protein whose absence is responsible for Batten disease, the most common inherited neurovisceral storage disease of childhood, was identified in 1995. The function of the protein, Cln3p, still remains elusive. We previously cloned theSaccharomyces cerevisiaehomolog to the humanCLN3gene, designatedBTN1,whose product is 39% identical and 59% similar to Cln3p. We report that yeast strains lacking Btn1p,btn1-Δ deletion yeast strains, are more resistant to -(−)-threo-2-amino-1-[p-nitrophenyl]-1,3-propanediol (ANP), in a pH-dependent manner. This phenotype is complemented in yeast by the humanCLN3gene. In addition, point mutations characterized in CLN3 from individuals with less severe forms of Batten disease, when introduced intoBTN1,altered the degree of ANP resistance. Severity of Batten disease due to mutations inCLN3and the degree of ANP resistance in yeast are related when the equivalent amino acid replacements in Cln3p and Btn1p are compared. These results indicate that yeast can be used as a model for the study of Batten disease.     

Stored dolichyl pyrophosphoryl oligosaccharides in Batten disease.

Each of the 3 childhood forms of Batten disease, juvenile (JB), late-infantile (LIB), and infantile (IB), have abnormally high brain concentrations of dolichyl pyrophosphoryl oligosaccharides (Dol-PP-OS). In this study, the carbohydrate portions of Dol-PP-OS were analysed: in JB and LIB, they range in size from Man2GlcNAc2 to Glc3Man9GlcNAc2, predominant components being Man5-7GlcNAc2 and Glc3Man7GlcNAc2. In IB, they range from Man6-9GlcNAc2, no glucose containing oligosaccharides being identified. In Batten disease, the main subcellular location of Dol-PP-OS is within storage material, where it represents up to 7% of the dry weight. [3H]-Mannose incorporation experiments with cultured fibroblasts show that synthesis of Dol-PP-OS in JB is normal. We infer that the glycosylation intermediate Glc3Man9GlcNAc2-PP-dolichol is synthesised normally within the endoplasmic reticulum in Batten disease, but that catabolic derivatives accumulate within the lysosomes. It is unclear whether this process is central to the pathogenesis of the disease, though in IB a defect in the release of mannose residues from Dol-PP-OS is a distinct possibility.     

The Immunopathology of Alzheimer's Disease and Some Related Disorders

Current evidence clearly indicates that elements of the immune system are involved in the pathogenesis of the principal lesions characterizing Alzheimer's disease (AD). Findings are in accord with features associated with both the innate and adaptive immune mechanisms involved in a predominantly local inflammatory response within the parenchyma. Many of the features are unique to AD, presumably related to the unusual properties of β amyloid protein. Remarkably, the brain holds the capacity to produce almost all the immune system mediators which largely seem to be generated by glia comprising both astrocytes and microglia. While a variety of humoral mediators including classical acute phase proteins (and serpins) are increased and released, the complement seems most intrinsically involved. The cellular response is elaborated by microglia which seem the main immunocompetent cells partaking in the response. These appear to function as pluripotent macrophages expressing both classes of MHC antigens. Further characterization of this interesting response to cerebral amyloidosis will be challenging.     

Alzheimer病与Parkinson病患者记忆损害的比较研究

目的：测查Alzheimer病、Parkinson病患者的记忆功能，了解这两种疾病病人记忆损伤的特征。方法：采用多维记忆评估量表中的12个分测验对30例原发性Parkinson病患者、30例临床诊断可能的Alzhdmer病患者及年龄、性别和教育程度与2个病人组相匹配的2个正常对照组进行外显记忆、内隐记忆及日常生活记忆等记忆功能的评定。结果：AD组在所有的分测验和记忆因子上均差于对照组；PD组在图画再认、数字广度、汉词回忆、图形再生、经历定向等分测验和记忆广度、再认记忆、自由回忆、日常记忆、外显记忆等记忆因子上均显著低于对照组：经以教育年限为协变量校正后发现。除自由组词、残图命名、数字广度、空间广度、汉词回忆、常识记忆、记忆广度、内隐记忆外，AD组在其余各分测验和记忆因子上均存显著差于PD病人组。结论：AD病人存在着广泛的记忆功能障碍：PD病人存在着工作记忆和策略记忆的障碍：两者的记忆功能障碍存在着明显的不同。     

Diagnosis of Neuronal Ceroid Lipofuscinosis (Batten Disease) by Electron Microscopy in Peripheral Blood Specimens

Neuronal ceroid lipopofuscinosis (Batten disease, NCL) represents a group of common childhood neurodegenerative diseases with a shared feature of deposition of abnormal metabolic products in neurons and other tissues, including peripheral blood lymphocytes. In most forms of NCL no specific enzyme defect is known and the diagnosis relies primarily on ultrastructural identification of characteristic membrane-bound inclusions containing the abnormal metabolic product. All buffy-coat specimens examined during a 7-year period (1997–2004) for the exclusion or confirmation of the diagnosis NCL were reviewed. From a total of 265 samples, 9 were inadequate and NCL was diagnosed in 56. Five showed granular osmophilic deposits of infantile Batten disease (NCL1), 10 showed curvilinear profiles of classical late infantile Batten disease (NCL2), and 17 showed vacuolated lymphocytes with fingerprint profiles, indicating classical juvenile Batten disease (NCL3). 24 samples (43%) demonstrated compact electron-dense deposits with fingerprint profiles in the absence of vacuolated lymphocytes, indicative of variant forms NCL. Ultrastructual examination of peripheral blood allows reliable and specific diagnosis of subtypes of Batten disease, including variants, and is a useful, minimally invasive test for the diagnosis of NCL in childhood.     

Sheep and other animals with ceroid-lipofuscinoses: their relevance to Batten disease.

Distinct pathological and histopathological changes distinguish the ceroid-lipofuscinoses from other storage diseases of humans and animals. These various disease entities likely reflect a variety of mutations of the same gene, or mutations of different genes associated with metabolism of the same or similar substrates. The disease in sheep most closely resembles the juvenile human disease. In it 50% of the lipopigment consists of subunit c of mitochondrial ATP synthase while the remaining constituents are considered normal for a lysosomal derived cytosome. The same subunit c has been shown to be also stored in affected English Setter, Border Collie, and Tibetan Terrier dogs, the Devon cow, and in the late infantile and juvenile human forms of disease but not in the infantile form. Thus it gives a chemical unity to at least some members of the group and allows a major conceptual change in regard to further directions of research.     

Rapid diagnostic test for the major mutation underlying Batten disease.

Batten disease is the most common progressive neurodegenerative disorder of childhood in western countries. A novel cDNA responsible for Batten disease has recently been identified. We have developed a rapid diagnostic solid phase minisequencing test to detect the major 1.02 kb deletion which is responsible for 81% of affected chromosomes in Batten disease worldwide. In Finland, 90% of Batten chromosomes carry the major deletion owing to the enrichment of the CLN3 gene in the isolated Finnish population.