Al Research Research Articles

Patient Reported Impact of Symptoms in Spinal Bulbar Muscular Atrophy (PRISM-SBMA) (S33.007)

Patient Reported Impact of Symptoms in Spinal Bulbar Muscular Atrophy (PRISM-SBMA) (S33.007)

Sheila Essey Award for ALS Research Goes to Australian Matthew Kiernan

Sheila Essey Award for ALS Research Goes to Australian Matthew Kiernan

Public-Private Collaboration in ALS Research by GUID Utilization Paves the Road to Patient-Centric Precision Research in Neurological Diseases (P4-5.001)

Public-Private Collaboration in ALS Research by GUID Utilization Paves the Road to Patient-Centric Precision Research in Neurological Diseases (P4-5.001)

Aaron Gitler, PhD, Received the Sheila Essey Award for Research in ALS. This Is Why.

Aaron Gitler, PhD, Received the Sheila Essey Award for Research in ALS. This Is Why.

Editorial introductions

Editorial introductions

THE STRUCTURAL BASIS FOR POLYPEPTIDE TRANSLOCATION BY THE HSP104 DISAGGREGASE

Heat shock protein (Hsp) 104, found in yeast, is a member of the Hsp100 class of molecular chaperones that contain highly conserved AAA+ (ATPases Associated with diverse cellular Activities) domains and serve critical roles in thermotolerance and protein quality control. Hsp104, and the bacterial homolog ClpB, form large hexameric‐ring structures that cooperate with the Hsp70 system to unfold and rescue aggregated protein states by active translocation of polypeptide substrates through a central channel. Hsp104 controls prion inheritance in yeast by recognizing and remodeling cross‐β structures of amyloid fibrils, such as those found in Sup35 prions. This function has led to studies identifying potentiated Hsp104 variants that reduce the toxicity of proteins linked to neurodegenerative diseases. Despite fundamental roles in protein quality control and promising therapeutic activity in rescuing amyloidogenic states, how Hsp104 and its family members function as powerful molecular motors to solubilize proteins is not fully understood. Furthermore, obtaining high‐resolution views of active complexes has been a significant challenge, thus a definitive structural mechanism for disaggregation has remained elusive. Here we have determined the cryo‐EM structure of wild type Hsp104 in the ATP state to 5.6 Å resolution. This work reveals an unprecedented two‐turn spiral architecture for the hexamer, identifying how the twelve AAA+ domains are coordinated for substrate translocation. The N‐terminal, C‐terminal and middle domains are observed in distinct conformations that explain functions in substrate engagement and ATP hydrolysis control. Remarkably, density for the substrate‐binding pore loops is identified to line the channel in a continuous arrangement that appears optimized for substrate transfer across the AAA+ domains, establishing a directional path for polypeptide translocation.Support or Funding InformationThis work was supported by National Institutes of Health (NIH) grant R01GM099836 (to J.S.). A.L.Y. is supported by an American Heart Association Predoctoral fellowship; M.E.J. is supported by a Target ALS Springboard Fellowship. J.S. is supported by a Muscular Dystrophy Association Research Award (MDA277268), the Life Extension Foundation, the Packard Center for ALS Research at Johns Hopkins University, and Target ALS. D.R.S. is supported by NIH grants R01GM109896, R01GM077430 and R01GM110001A.

Western Faculty Profile: Dr. Michael J. Strong

Dr. Michael Strong is the Dean of the Schulich School of Medicine and Dentistry. He serves as the Arthur J. Hudson Chair in ALS Research and is an accomplished neurologist and a decorated researcher. Dr. Strong spent his undergraduate years at Queens university, graduated Queen's School of Medicine, and attended Western University to pursue further training in Neurology.

A New Phase in ALS Research

In this issue of Structure, Conicella etal. (2016) present evidence that the low complexity C-terminal region of TDP-43 undergoes liquid-liquid phase separation. ALS-associated mutations alter this phase separation process, providing a possible mechanism for the pathology caused by these TDP-43 mutations. The work is strongly supportive of toxic loss of RNA processing function in ALS.

Henry Agard Wallace - The First Vice-President to Develop Amyotrophic Lateral Sclerosis and the Early ALS Research Program at the National Institutes of Health - "Reflections of an ALSer" (P2.399)

Henry Agard Wallace - The First Vice-President to Develop Amyotrophic Lateral Sclerosis and the Early ALS Research Program at the National Institutes of Health - "Reflections of an ALSer" (P2.399)

Platform for Clinical Trials Data Integration and Sharing as a Unique Industry, Academic, and Foundation Collaboration Resource in ALS Research (P01.091)

Platform for Clinical Trials Data Integration and Sharing as a Unique Industry, Academic, and Foundation Collaboration Resource in ALS Research (P01.091)

UBQLN2 Mutations in ALS and ALS/Dementia: A Genetic, Functional and Histopathological Analysis (S05.006)

Objective: To identify the genetic defect causing dominant X-linked ALS and ALS/dementia, and characterize the functional and pathological determinants. Background Most cases of ALS are sporadic but about 5-10% are familial. Mutations in SOD1, TDP43 and FUS account for approximately 30% of classic familial ALS. The causes of the remaining cases of familial ALS and of the vast majority of sporadic ALS are unknown. Despite extensive studies of previously identified ALS-causing genes, the pathogenic mechanism underlying motor-neuron degeneration in ALS remains largely obscure. Dementia, usually of the frontotemporal lobar type, may occur in some ALS cases. It is unclear whether ALS and dementia share common aetiology and pathogenesis in ALS/dementia. More than a decade ago, we had linked a large ALS family to the pericentric region of the X chromosome. Design/Methods: Detailed mapping was done with dense microsatellite markers and Illumina Sentrix HumanHap300 Genotyping BeadChip. Candidate genes were sequenced using Beckman Coulter CEQ 8000 DNA analysis system. Immunohistochemistry and light and confocal microscopy were performed according to standard protocols. Neuro2a and SHSY-5Y cells were transiently co-transfected with a ubiquitin-proteasome system (UPS) reporter plasmid (Ub-G76V-GFP) and pIRES2-DsRed2 dual expression vectors containing either wildtype or mutant UBQLN2 and analyzed using a MoFlo cell sorter and Summit software. Results: We show mutations of ubiquilin2, a ubiquitin-like protein, in five families with ALS and ALS/dementia. We also show that inclusions containing ubiquilin2 are a common pathological feature in a wide spectrum of ALS and ALS/dementia. Functional studies indicate an impairment of ubiquitin-mediated proteasomal degradation in cells expressing mutant ubiquilin2. Conclusions: These data provide evidence for an impairment of protein turnover in the pathogenesis of ALS and ALS/dementia. Further elucidation of these processes may be central to the understanding of pathogenic pathways. These pathways should provide novel molecular targets for the design of rational therapies for these disorders. Supported by: The National Institute of Neurological Disorders and Stroke (NS050641), the Les Turner ALS Foundation, the Vena E. Schaff ALS Research Fund, the Harold Post Research Professorship, the Herbert and Florence C. Wenske Foundation, the David C. Asselin MD Memorial Fund, the Help America Foundation and the Les Turner ALS Foundation/Herbert C. Wenske Foundation Professorship. F.F. has support from NIH (T32 AG20506). K.A. is a postdoctoral fellow of the Blazeman Foundation for ALS. G.H.G. received travel funds from MND Scotland. Disclosure: Dr. Fecto has nothing to disclose. Dr. Deng has nothing to disclose. Dr. Chen has nothing to disclose. Dr. Hong has nothing to disclose. Dr. Boycott has nothing to disclose. Dr. Gorrie has nothing to disclose. Dr. Siddique has nothing to disclose. Dr. Yang has nothing to disclose. Dr. Shi has nothing to disclose. Dr. Zhai has nothing to disclose. Dr. Jiang has nothing to disclose. Dr. Hirano has nothing to disclose. Dr. Rampersaud has nothing to disclose. Dr. Jansen has nothing to disclose. Dr. Donkervoort has nothing to disclose. Dr. Bigio has nothing to disclose. Dr. Brooks has received personal compensation for activities with Avanir Pharmaceuticals, Bayer Healthcare Pharmaceuticals, Biogen Idec, Genentech, Inc., and Teva Neuroscience. Dr. Brooks has received research support from Avanir Pharmaceuticals, Biogen Idec, NINDS, Novartis, and Teva Neuroscience. Dr. Ajroud has nothing to disclose. Dr. Sufit has nothing to disclose. Dr. Haines has nothing to disclose. Dr. Mugnaini has nothing to disclose. Dr. Pericak-Vance has nothing to disclose. Dr. Siddique has nothing to disclose.

Tradiciones vs. Bienestar Animal: Propuesta de la juventud a Naciones Unidas

In April the Postgraduate Degree Animals, Law and Society and the ALS Research Group of the UAB participated at a simulation of the UNESCO’s working procedure, within the framework of the Catalonia Model of United Nations (C’MUN 2011). This document summarizes a general evaluation of the final resolution agreed at that commitee on the topic ‘Traditions vs. Animal Welfare’, and which will be sent to the United Nations Secretary-General as the proposal of the youth of the world for the international community.

Proposed BioRepository platform solution for the ALS research community

ALS is a rare disorder whose cause and pathogenesis is largely unknown ( 1 ). There is a recognized need to develop biomarkers for ALS to better understand the disease, expedite diagnosis and to facilitate therapy development. Collaboration is essential to obtain a sufficient number of samples to allow statistically meaningful studies. The availability of high quality biological specimens for research purposes requires the development of standardized methods for collection, long-term storage, retrieval and distribution of specimens. The value of biological samples to scientists and clinicians correlates with the completeness and relevance of phenotypical and clinical information associated with the samples ( 2 , 3 ). While developing a secure Web-based system to manage an inventory of multi-site BioRepositories, algorithms were implemented to facilitate ad hoc parametric searches across heterogeneous data sources that contain data from clinical trials and research studies. A flexible schema for a barcode label was introduced to allow association of samples to these data. The ALSBank™ BioRepository platform solution for managing biological samples and associated data is currently deployed by the Northeast ALS Consortium (NEALS). The NEALS Consortium and the Massachusetts General Hospital (MGH) Neurology Clinical Trials Unit (NCTU) support a network of multiple BioBanks, thus allowing researchers to take advantage of a larger specimen collection than they might have at an individual institution. Standard operating procedures are utilized at all collection sites to promote common practices for biological sample integrity, quality control and associated clinical data. Utilizing this platform, we have created one of the largest virtual collections of ALS-related specimens available to investigators studying ALS.

The CEO of ALS Research

The CEO of ALS Research

Modifiable barriers to enrollment in American ALS research studies

Enrollment in ALS research studies is surprisingly low. Here we report on two online patient surveys that help identify some of the reasons. These include failure to invite patients to enroll, especially patients who have already participated in prior studies. Also included are patient concerns about the cost of participation, and confusion about several aspects of studies being offered. Along with prior work, these data suggest specific steps that can be taken to improve enrollment.

A new editor for the “Black but not bleak” journal – ALS research is coming of age

A new editor for the “Black but not bleak” journal – ALS research is coming of age

ALS Research Group (ALSRG): Second meeting, a summary report

ALS Research Group (ALSRG): Second meeting, a summary report

Novel trends in orphan market drug discovery: amyotrophic lateral sclerosis as a case study

As new lead discovery technologies of high throughput screening and rational drug design have been incorporated into pharmaceutical and biotechnology drug discovery programs, researchers have focused on the applying these new technologies in diseases traditionally neglected by for-profit drug discovery efforts. This article reviews general trends in orphan disease lead discovery, identifies best practices of orphan market drug discovery and provides an overview of recent ALS lead discovery programs and drug development according to these metrics. Best practices in orphan market drug discovery embodied by programs like the NIH Anticonvulsant Screening Program include the (1) management of timelines and priorities, (2) engagement of for-profit partners, (3) creative application of technology, (4) collaboration, and (5) flexibility. Recent trends in ALS lead discovery have been shaped not only by the predominance of animal models of disease over in vitro models, but also by the successes and best practices of these earlier orphan market drug discovery programs. The ALS Treatment Initiative, the Johns Hopkins Center for ALS Research, the ALS Association, and the ALS Therapy Development Foundation have all initiated lead discovery programs in the past several years which seek to utilize existing experimental models of the disease and challenge assumptions about the linear nature of the lead discovery and development process. The compounds currently in clinical evaluation for ALS were identified as leads from a variety of sources, further reinforcing the transforming effect these new lead discovery programs have had on drug discovery and development in ALS. We conclude our review with an overview of the challenges and opportunities lead discovery in ALS currently faces, ultimately concluding that ALS lead discovery, and indeed orphan market drug discovery in general, would most benefit from more centralized lead discovery management, expanded national access to core facilities for lead discovery, and matrixed simultaneous screening of multiple compounds for multiple neglected diseases.

Novel trends in orphan market drug discovery: amyotrophic lateral sclerosis as a case study.

As new lead discovery technologies of high throughput screening and rational drug design have been incorporated into pharmaceutical and biotechnology drug discovery programs, researchers have focused on the applying these new technologies in diseases traditionally neglected by for-profit drug discovery efforts. This article reviews general trends in orphan disease lead discovery, identifies best practices of orphan market drug discovery and provides an overview of recent ALS lead discovery programs and drug development according to these metrics. Best practices in orphan market drug discovery embodied by programs like the NIH Anticonvulsant Screening Program include the (1) management of timelines and priorities, (2) engagement of for-profit partners, (3) creative application of technology, (4) collaboration, and (5) flexibility. Recent trends in ALS lead discovery have been shaped not only by the predominance of animal models of disease over in vitro models, but also by the successes and best practices of these earlier orphan market drug discovery programs. The ALS Treatment Initiative, the Johns Hopkins Center for ALS Research, the ALS Association, and the ALS Therapy Development Foundation have all initiated lead discovery programs in the past several years which seek to utilize existing experimental models of the disease and challenge assumptions about the linear nature of the lead discovery and development process. The compounds currently in clinical evaluation for ALS were identified as leads from a variety of sources, further reinforcing the transforming effect these new lead discovery programs have had on drug discovery and development in ALS. We conclude our review with an overview of the challenges and opportunities lead discovery in ALS currently faces, ultimately concluding that ALS lead discovery, and indeed orphan market drug discovery in general, would most benefit from more centralized lead discovery management, expanded national access to core facilities for lead discovery, and matrixed simultaneous screening of multiple compounds for multiple neglected diseases.

Genetics of familial ALS and consequences for diagnosis. French ALS Research Group.

Familial amyotrophic lateral sclerosis (fALS) is a well-recognised condition that accounts for almost 10% of all cases of ALS. Most cases are now known to be transmitted by an autosomal dominant trait. When fALS is compared clinically to sporadic ALS, 20% of cases manifest atypical features such as pain, paraesthesia or urgency micturition. Moreover, a disease duration of over 10 years, with very slow progression, appears to occur almost exclusively in cases of fALS. Studies of superoxide dismutase (SOD1) mutations in fALS have shown that the disease may be multidegenerative, with oculomotor or cerebellar involvement. Molecular genetics has also demonstrated that not all SOD1 mutations have a dominant influence, and the detailed description of the Scandinavian D90A homozygous mutation is very informative in this regard. Misdiagnosis of fALS can be attributed to one of the following situations: (i) atypical phenotype ALS with a multidegenerative profile; (ii) unusually long lasting ALS with mild motor neuron involvement; (iii) significant clinical heterogeneity between affected family members; (iv) low reliability of family history; (v) existence of an unknown or unexpected mode of transmission; and (vi) other multidegenerative disorders with motor neuron involvement. Pedigrees and fALS cases corresponding to these situations are presented.