Objectives of the Presentation

 Recognize movement disorders beyond cerebellar ataxia

 Apply current knowledge of genomics to gene discovery

 Utilize knowledge of genetic diseases to understand acquired disease

Overview of the Issue

 Spontaneous hereditary neurodegenerative diseases are common in dogs

 What can hereditary diseases teach us about more common acquired diseases?

 Why can spontaneous canine diseases be more beneficial to understanding human disease than mouse models?

 How will these studies improve therapies for humans and dogs?

Additional Detail

In the hereditary cerebellar ataxias, the control of the range and force of movement is disrupted by biochemical or structural changes within the cerebellum. A quadruped such as a dog is inherently more stable than a biped like a human. As a result, dogs can suffer much more severe disruption of coordination and still be functional. Some hereditary movement disorders, however, affect more than the cerebellum, leading to more severe motor compromise.

The basal nuclei (ganglia) are a collection of gray matter areas located in the basal forebrain. The organization and complexity of the basal nuclei varies between species. While the cerebellum is involved in fine-tuning movement, the basal nuclei are more involved in motor planning and initiation. Thus diseases of the basal nuclei can lead to involuntary movements (hyperkinetic disorders) or difficulty initiating movement (hypokinetic disorders). Huntington's disease in humans leads to a degeneration of the caudate nucleus and involuntary movements (chorea). Parkinson's disease leads to degeneration of the dopaminergic cells that project to the caudate nucleus from the substantia nigra. While the resting tremor are the most obvious manifestation of parkinsonism, it is the difficulty initiating movements (brady- or hypokinesia) and the loss of balance resulting in falls which are devastating to Parkinson's patients. Some human movement disorders result in degeneration of several different portions of the motor system and are referred to as multiple system degenerations or sometimes as Parkinson's plus syndromes.

Figure 1: The basal nuclei are motor areas deep within the brain that are involved in the initiation and planning of movements.

Though the cerebellar ataxias are the most common hereditary movement disorders in animals, others are being more commonly recognized. The best studied is canine multiple system degeneration (CMSD) in Kerry Blue terriers and Chinese crested dogs. The condition has been referred to by a variety of names in different publications and is called PNA (progressive neuronal abiotrophy) by breeders. Affected dogs develop a classic cerebellar ataxia beginning about 3 months of age. The cerebellar signs will remain stable for up to a year or more, and dogs euthanized at this stage of the disease show only cerebellar atrophy. In the later stages of the disease, however, the dogs begin having difficulty initiating movement. They will freeze and then lurch forward when they are finally able to move. They develop severe balance problems and fall frequently. Eventually they are unable to walk and die of complication of their disease if they are not euthanized. In these later stages of the disease, degeneration of the basal nuclei is also apparent and preliminary results show loss of dopaminergic cells. Thus CMSD is similar to the Parkinson's plus syndromes of humans.

The gene for CMSD in these breeds has been mapped to a small region of canine chromosome 1 which contains the canine equivalent of the human PARK2 gene. Mutations in PARK2 in humans cause the most common form of familial Parkinson's disease, autosomal recessive juvenile Parkinsonism. The PARK2 gene codes for the protein parkin. Parkin is a key component in the system which recycles worn out or damaged proteins in cells, the ubiquitin-proteasome system. When this system malfunctions, these damaged proteins can no longer be recycled properly and they can accumulate within the cells interfering with their function. In addition to PARK2, mutations in two other proteins involved in the ubiquitin-proteasome system also lead to familial forms of Parkinsonism in humans.

The classic Parkinson's disease that affects over a half a million Americans is a sporadic, old-age degenerative disease, not a familial disease. So why study rare hereditary forms of the disease? In spite of intensive research, the cause of sporadic Parkinson's disease has remained elusive. While symptomatic therapies can improve function, none stop the progression of the disease. Studying the cause of dopaminergic cell loss in hereditary forms of the disease may shed light on the more common sporadic disease. In the classic Parkinson's disease, there is an accumulation of abnormal proteins. This suggests that the ability of brain cells to recycle damaged proteins may be affected in the sporadic as well as the hereditary disease. This provides an avenue to investigate the causes of that impairment and suggests new therapies that will stop the progression of disease rather than just ameliorating the symptoms.

The traditional experimental approach to determining how mutations cause disease and how therapies could reverse those effects is to utilize a knock-out mouse model of the disease. In the knock-out mouse, the gene in question is experimentally inactivated (knocked out). The resultant strain can then be studied for the pathogenesis of the disease and the effects of potential therapies. Unfortunately, mice differ significantly in the size, complexity, and organization of their nervous systems. In the case of the PARK2 gene for example, knock out mice show no ill effects of losing parkin function. Thus they cannot provide any insight into the role of that system in the human disease.

In contrast, dogs with hereditary neurodegenerative diseases present to the veterinary neurologist because they have a clinical disease. With modern diagnostic methods, the disease can be diagnosed and the underlying genetic defect identified. Once the gene has been identified, a DNA test can help breeders avoid producing affected dogs in the future. By studying the spontaneous disease in these dogs, we can identify the role of these genes and the pathways involved in disease and investigate novel therapeutic approaches that can benefit the canine as well as the human patients.

Summary

 In Canine Multiple System Degeneration, multiple portions of the motor system degenerate producing cerebellar ataxia and parkinsonism

 The area where the gene responsible has been mapped includes the PARK2 gene, the most common cause of familial Parkinsonism in humans.

 Understanding how this mutation leads to disease in dogs could shed light on the cause of Parkinson's disease in humans

 The spontaneous canine disease has distinct advantages over the artificially created "knock out" mice.

References/Suggested Reading

1.  A. deLahunta and D. R. Averill. Hereditary cerebellar cortical and extrapyramidal nuclear abiotrophy in Kerry blue terriers. Journal American Veterinary Medical Association 168:1119-1124, 1976.

2.  F. A. Metler and L. J. Goss. Canine chorea due to striatocerebellar degeneration of unknown etiology. Journal American Veterinary Medical Association 108:377-384, 1946.

3.  D. L. Montgomery and R. W. Storts. Hereditary striatonigral and cerebello-olivary degeneration of the Kerry blue terrier: I. Gross and light microscopic central nervous system lesions. Veterinary Pathology 20:143-159, 1983.

4.  D. P. O'Brien, G. S. Johnson, R. D. Schnabel, S. Khan, J. R. Coates, G. C. Johnson, and J. F. Taylor. Genetic mapping of canine multiple system degeneration and ectodermal dysplasia Loci. Journal of Heredity 96 (7):727-34, 2005.

5.  D. P. O'Brien. Molecular Approaches to Hereditary Neurodegenerative Diseases. Proceedings 24th Annual ACVIM Forum. Louisville KY:308-310, 2006.