HSP research- where have we come from and where are we going? E Evan Reid

3 Phases of HSP Research Clinical

The Grandfathers of HSP Research Adolph Strumpell b d.1925 Maurice Lorrain b.1866 – d.?

The Mother of HSP Research

Clinical Phase Clinical features of HSP defined – distinction of “pure” versus “complex” HSP – definition of core features – understanding of pathological anatomy – understanding of modes of inheritance of HSP – basic definition of many of the complex subtypes

3 Phases of HSP Research Clinical Genetic

Genetic Phase Sue Kenwrick

3 Phases of HSP Research Now 50 known genes Next generation sequencing

Impact of next generation sequencing

3 Phases of HSP Research Now 50 known genes Maybe in total? Modifier genes will also be identified Next generation sequencing

3 Phases of HSP Research Clinical Genetic

Each of these genes presents a challenge and an opportunity

3 Phases of HSP Research Clinical Genetic Biological and treatment

The insides of a cell Head Office Nucleus with DNA Manufacturing Endoplasmic reticulum and Golgi Export secretion Import of components endosomes Instructions Power generators Mitochondria Transport and logistics Sales and Market Research Plasma membrane receptors Transport and logistics Signaling Reuse Recycling QC

Microtubules are rails for cargo transport

The insides of a neuron

Hereditary Spastic Paraplegia Pathology Caused by distal degeneration of the longest axons of the corticospinal tract Distal degeneration

Long axons are a mixed blessing……. -Length enables rapid response to environment

Long axons are a mixed blessing……. -But complex machineries are required to sort and transport cargoes to the distal end of the axon

HSP proteins involved in membrane traffic and transport

Spastin is a microtubule severing enzyme spastin + tubulin

Spastin severs microtubules Why do cells need to sever microtubules? Why does lack of microtubule severing cause HSP?

Spastin and HSP Research in Cambridge: Cell Biology Animal models Human Studies HSP clinic Next generation sequence DDD Membrane traffic High res. microscopy Proteomics Stem cell technology Gene editing Interactomes Mice Zebrafish Flies Translation

The insides of a neuron

Spastin helps shape the endoplasmic reticulum

The insides of a neuron

Endosomes tubulate in the absence of spastin

Is the tubulation phenotype relevant to axons? Jamile Hazan and Coralie Fassier, Paris

Is the tubulation phenotype relevant to axons?

How could this lead to disease? BIN Recycle

How might abnormal tubulation cause axonopathy? Wang X, Shaw RW, Tsang HT, ReidE, O’Kane CJ. (2007) Nature Neuroscience, 10: In at least 5 fly or zebrafish models of HSP, distal axonal abnormalities are caused by upregulated Bone Morphogenetic Protein signaling Upregulated Bone Morphogenetic Protein (BMP) signaling in HSP Small molecule BMP inhibitors are already available A potential treatment strategy?

An overview of trends in HSP research Further gene identification will be rapid and fruits of this will be of immediate benefit to HSPers We are developing a thorough knowledge of basic cellular functions of many HSP proteins Many HSP proteins have are inter-related functions Animal models for many HSPs are progressing quickly- these will allow us to study functions in axons Stem cell models are beginning to be used- potentially an exciting development Potential treatment avenues have been identified The need for treatment is urgent, but careful and thorough science is critical

Duchenne muscular dystrophy survival curves Near Future Cambridge HSP clinic Genetics Neurological Rehabilitation and support NHS next generation sequencing panels = where there is a need, most patients will have a molecular diagnosis Advice on inheritance pattern, predictive testing etc. Orthotics Botox Intrathecal baclofen FES Clinical assessment Other neurological investigations ….yet there is no “treatment” for DMD

Acknowledgements REID Lab: Rachel Allison Jennifer Lumb James Connell Tim Newton Paris Jamile Hazan Coralie Fassier Matt Seaman