A New Approach to Neurodegenerative Diseases

Gene Solution’s contention is that a number of apparently, sporadic neurologic diseases (Alzheimer’s, Parkinson’s, ALS (Amyotrophic Lateral Sclerosis aka Motor Neurone Disease (UK) and  Lou Gehrig’s Disease (US)), schizophrenia) are in fact inherited but via the mitochondrial rather than the nuclear genome. This means that the diseases are primary to the mitochondria and originate there.  Everything else (amyloid, Lewy bodies, oxidative stress, etc) is downstream of various, primary (genetic) mitochondrial dysfunction. This new therapeutic approach is therefore built around the concept of heteroplasmy (more than one type of mt-DNA in a cell) and around the unique properties of mtDNA in the cell cycle. Unlike the case with nuclear (chromosomal) genes, mtDNA replicates continuously and more or less independently of the cell cycle. This is true even in terminally differentiated cells such as neurons. mtDNA-undergoes slow and continuous turnover. This fact plus the fact that an individual harbours a mixture of wildtype and mutant mtDNA offers an unprecedented therapeutic approach: selectively slow the replication of the mutant mtDNA and allow the normal mtDNA to repopulate the cells over a period of time. If the burden of mutant mtDNA can be driven down over time, disease progression can be halted and even prevented if symptoms have not yet occurred. Leber’s Hereditary Optic Neuropathy has been a useful and non-controversial prototype for exploration of this thesis and the creation of a generic ligand identification process to address more important diseases.  This disorder is unquestionably inherited via the mitochondrial genome.  It is a systemic (body-wide) disorder yet in most patients, neurologic dysfunction is confined to optic nerve.  If a specific set of mitochondria DNA mutations causes focal optic nerve disease it is not unreasonable to ask whether or not some other mutation(s) target substantia nigra (Parkinson’s) or hippocampus (Alzheimer’s) or anterior horn cells (ALS).  Furthermore, Leber’s disease may have a very long latency and not become symptomatic until well into adulthood demonstrating that these biochemical/genetic lesions may not cause problems until late in life as is the case with many degenerative CNS diseases

A first test of this hypothesis is to ask whether or not these diseases involve an electron transport chain (ETC) lesion because all mitochondrial gene products are components of the ETC.  AD, PD, ALS, schizophrenia, and others all involve systemic, specific ETC lesions.  These biochemical lesions can be related back to the specific disease phenotype through the study of various inhibitors designed to reproduce the specific enzyme defect in animals (e.g. the mitochondrial toxin MPTP which causes PD in humans and animals).

The origin of these ETC defects in mitochondrial DNA was demonstrated by transfer of patient mitochondria (hence mitochondrial DNA) into cultured cells depleted of their own mitochondrial DNA.  These experiments reproduce not only the specific ETC lesion seen in patients they also reproduce many important, secondary events such as amyloid production.  Transfer of AD mitochondrial DNA into cultured cells results in secretion of Ass 1-40 and 1-42, the specific amyloid fragments associated with naturally occurring AD and a similar experiment done with PD mitochondria leads to Lewy body formation.

This research has uncovered a series of unique targets that we believe to be drugable.  We further believe that dealing with these targets pharmacologically will halt disease progression and will probably prevent the disease from occurring if pre-symptomatic patients can be identified.

Current  position

Using LHON as a generic prototype, the technology enabling rapid identification of novel neurological disease-associated mutations and diagnosis of central nervous system diseases based on these mutations has been established. An extensive database of mitochondrial gene mutations has been assembled and the unique category of genetic disruptions that cause known cellular malfunction have been identified and demonstrated. The point mutation for Leber’s disease is known.
Work to demonstrate mitochondrial gene involvement in other diseases has reached various stages of completion:

  • The mutations associated with, and potentially causative of Parkinson’s disease have been identified. These mutations have been validated through blinded analysis of Parkinson’s Disease patients and control samples in both brain tissue and blood platelets
  • Alzheimer’s disease mutation discovery is partially complete and the key region of interest defined for further sequencing.
  • Identification of schizophrenia mutations and IP creation are at a very early stage.
  • A Gene Solutions chemistry effort has started and is being progressed in two directions: compounds made by a generic process for creating ligands that bind the regions of specific point mutations. These (peptide-like) compounds are not drug-like but are designed to serve 3 purposes: as demonstrators of mechanism; as the basis of a displacement assay and as probes of structure-activity relationships to guide the production of tractable drug leads. In parallel work on a bioisosterically equivalent series of “Lipinski Compliant” compounds to provide tractable drug leads is being carried out.

Relevant Papers

  1. Parker WD Jnr, Parks JK, Swerdlow RH, Complex I deficiency in Parkinson’s disease frontal cortex. Brain Res, 2008, Jan 16, 1189215-8
  2. McAlister J, Ghosh S, Berry D, Park M, Sadeghi S, Wang KX, Parker WD, Swerdlow RH. Effects of meantine on mitochondrial function. Biochem Pharmacol 2008 Feb15, 75(4), 956-64
  3. Smigrodzki R, Goetzel B, Pennachin C, Coelho L, Proadocimi F, Parker WD Jnr. Genetic algorithm for analysis of mutations in Parkinson’s disease. Artif Intell Med, 2006 35(3) 227-41
  4. Parker WD Jnr, Parks JK. Mitchondrial mutations in idiopathic Parkinson’s disease. Biochem Biophys Res Commun., 2006, Jan 21, 326(3) 667-9
  5. Smigrodzki R, Parks J, Parker WD. High frequency mitochondrial Complex I mutations in parkinsons disease and aging. Neurobiol Aging, 2004, 25(10), 1273-81.
  6. Trimmer PA, Borland MK, Keeney PM, Bennett JP Jnr, Parker WD Jnr. Parkinson’s disease transgenic mitochondrial cybrids generate Lewy inclusion bodies. J Neurochem, 2004, 88(4), 800-12.
  7. Swerdlow RH, Parks JK, Pattee G, Parker WD Jnr. Role of mitochondria in amyotrophic lateral sclerosis. Amyotroph Lateral Scler Other Motor Neuron Discord. 2000, 1(3), 185-90.