The goal of this assignment is to familiarize you with the process  going from the characterization of a disease in human patients, to the  identification of a mutated gene causing it, to the use of a mouse model  to investigate how this mutation is causing     the disease. You will learn about the spinocerebellar ataxia 1  (SCA1) genetic disease as an example of such a process.

This assignment is inspired by and uses content from, the lecture “

A Healthy Nervous System: A Delicate Balance

” on     BioInteractive. Watch the video, (it may also be useful to

download the transcript

for reference)     and answer the questions below. 

Question 1:  Based on this video, describe the symptoms of the SCA1 disease.

SCA1 is a familial disease as indicated by the pedigree analysis chart shown on the video and in the image below.  

Question 2:  Explain  how to read the chart by indicating what the squares and circles  represent and what is the difference between filled and hollow shapes.  

Question 3:  Discuss what conclusions can be drawn from the pedigree eg  assuming that the disease is caused by the mutation of one single gene,  do you think this mutation is recessive or dominant? Are the affected  individuals more likely to be heterozygous or homozygous for this  mutation? Is the disease affecting equally men and women? For each  conclusion, make sure to explain how it is supported by the pedigree.

The

Online Mendelian Inheritance in Man (OMIM) database

is  a frequently updated database of human genes and genetic diseases.   Search for SCA1 on OMIM. Read quickly through the page to get a general  idea of the types of information that can be found on it and how they  are presented. Identify the gene whose mutation is responsible for the  SCA1 disease, search for it on OMIM and have a quick look at the  corresponding page.

Question 4:  Based  on the descriptions in OMIM and the information from the video,  indicate what genetic mutation is responsible for the SCA1 disease and  what consequence it has on protein primary structure.

Question 5:  Which organ and cell type  are primarily affected by the mutation? Is this consistent with the  symptoms observed in SCA1 patients?

Mice are generally a good model  for human diseases, if you wish, you can read more about the benefits of  the mouse model on The Jackson Laboratory website 

Advantages of the mouse as a model organism

.             

Mouse models of SCA1 have been developed and helped researchers to understand this disease and to experiment new treatments. 

Question 6:  From the video describe the phenotype of the SCA1 mouse. Is it similar to symptoms observed in SCA1 patients?

Question 7:  Is SCA1 considered to be caused by a loss of function of the protein affected, or is it thought to be due to another mechanism?

Question 8:   Based on the findings from the mouse model, researchers then developed  an SCA1 model in Drosophila – what are the advantages of using a  Drosophila model over a mouse one 

Question 9:  Using  the Drosophila model of SCA1, what was the protein kinase they found to  be implicated in SCA1 associated neurodegeneration and why is this  knowledge useful with respect to treating the disease?