[advance online publication in the journal Brain, 6/2015]
Mutations in more than 70 distinct loci and more than 50 mutated gene products have been identified in patients with hereditary spastic paraplegias, a diverse group of neurological disorders characterized predominantly, but not exclusively, by progressive lower limb spasticity and weakness resulting from distal degeneration of corticospinal tract axons. Mutations in the SPAST (previously known as SPG4) gene that encodes the microtubule-severing protein called spastin, are the most common cause of the disease. The aetiology of the disease is poorly understood, but partial loss of microtubule-severing activity resulting from inactivating mutations in one SPAST allele is the most postulated explanation. Microtubule severing is important for regulating various aspects of the micro- tubule array, including microtubule number, length, and mobility. In addition, higher numbers of dynamic plus-ends of microtubules, resulting from microtubule-severing events, may play a role in endosomal tubulation and fission. Even so, there is growing evidence that decreased severing of microtubules does not fully explain HSP-SPG4. The presence of two translation initiation codons in SPAST allows synthesis of two spastin isoforms: a full-length isoform called M1 and a slightly shorter isoform called M87. M87 is more abundant in both neuronal and non-neuronal tissues. Studies on rodents suggest that M1 is only readily detected in adult spinal cord, which is where nerve degeneration mainly occurs in humans with HSP-SPG4. M1, due to its hydrophobic N-terminal domain not shared by M87, may insert into endoplasmic reticulum membrane, and together with reticulons, atlastin and REEP1, may play a role in the morphogenesis of this organelle. Some mutated spastins may act in dominant-negative fashion to lower microtubule-severing activity, but others have detrimental effects on neurons without further lowering microtubule severing. The observed adverse effects on microtubule dynamics, axonal transport, endoplasmic reticulum, and endosomal trafficking are likely caused not only by diminished severing of microtubules, but also by neurotoxicity of mutant spastin proteins, chiefly M1. Some large deletions in SPAST might also affect the function of adjacent genes, further complicating the aetiology of the disease.
Giving Tuesday was a great start on our year end goal. So far we have raised over $37,000. Our anonymous donor will match every donation dollar for dollar up to $175,000 until January 15, 2017. That's right, every donation you make will be doubled so you will receive twice as much satisfaction and double the number of people you will help with your wonderful and most appreciated generosity. This is 40% more than was matched last year so we are asking everyone to stretch your giving as well to make sure we use every nickel of this match. We can do it!
When Clinical Trials begin in 2017 it may require as many people as possible for the Clinical Trial to be effective. If you have HSP or PLS, please add your information to our data base so we can keep you informed. We are missing a lot people's email address, so if you just want to add your email address. just enter your name, address and email and we'll add it. That way, we will be able to reach you quickly at a lower cost. Your privacy is very important to us. We will never share any of your information with any individual or company without your permission.
93 cents of every dollar you donate goes into our mission of research and service. 4 cents goes to fundraising and 3 cents goes to data management and general expenses. Our all volunteer Scientific Advisory Board makes sure that we are supporting only the very best research projects on the planet. The Spastic Paraplegia Foundation is an all volunteer run foundation. Our highly skilled staff, Scientific Advisory Board, Medical Advisors - CPA, Attorney, President, Board Members - all of us are working hard every day probono because we strongly believe in this cause. We know we can get to our goal if we all do our very best. We ask you to please join in our efforts by making a donation.