lysosomal storage disease
Posted on by Lawrence Tabak, D.D.S., Ph.D.
A common theme among parents and family members caring for a child with the rare Batten disease is “love, hope, cure.” While inspiring levels of love and hope are found among these amazing families, a cure has been more elusive. One reason is rooted in the need for more basic research. Although researchers have identified an altered gene underlying Batten disease, they’ve had difficulty pinpointing where and how the gene’s abnormal protein product malfunctions, especially in cells within the nervous system.
Now, this investment in more basic research has paid off. In a paper just published in the journal Nature Communications, an international research team pinpointed where and how a key cellular process breaks down in the nervous system to cause Batten disease, sometimes referred to as CLN3 disease . While there’s still a long way to go in learning exactly how to overcome the cellular malfunction, the findings mark an important step forward toward developing targeted treatments for Batten disease and progress in the quest for a cure.
The research also offers yet another excellent example of how studying rare diseases helps to advance our fundamental understanding of human biology. It shows that helping those touched by Batten disease can shed a brighter light on basic cellular processes that drive other diseases, rare and common.
Batten disease affects about 14,000 people worldwide . For those with the juvenile form of this inherited disease of the nervous system, parents may first notice their seemingly healthy child has difficulty saying words, sudden problems with vision or movement, and changes in behavior. Tragically for parents, with no approved treatments to reverse these symptoms, the disease will worsen, leading to severe vision loss, frequent seizures, and impaired motor skills. The disease can be fatal as early as late childhood or the teenage years.
Batten disease also goes by the more technical name of juvenile neuronal ceroid lipofuscinosis. Using this technical name, it represents one of the more than 70 medically recognized lysosomal storage disorders.
These disorders share a breakdown in the ability of membrane-bound cellular components, known as lysosomes, to degrade the molecular waste products of normal cell biology. As a result, all this undegraded material builds up and eventually kills affected cells. In people with Batten disease, the lost and damaged cells cause progressive dysfunction within the nervous system.
Researchers have known for a while that the most common cause of this breakdown in people with Batten disease is the inheritance of two defective copies of a gene called CLN3. As mentioned above, what’s been missing is a more detailed understanding of what exactly a working copy of the CLN3 gene does and how its loss leads to the changes seen in those with this condition.
Hoping to solve this puzzle was an NIH-supported basic research team led by Alessia Calcagni and Andrea Ballabio, Baylor College of Medicine and Texas Children’s Hospital, Houston, and Telethon Institute of Genetics and Medicine, Naples, Italy.
As described in their latest paper, the researchers first generated an antibody that allowed them to visualize where in cells the protein encoded by CLN3 is found. Their studies unexpectedly showed that this protein has a role outside, not inside, the cell’s estimated 50-to-1,000 lysosomes. Before reaching the lysosomes, the protein first moves through another cellular component called the Golgi body, where many proteins are packaged.
They then identified all the other proteins that interact with the CLN3 protein in the Golgi body and elsewhere in the cell. Their data showed that CLN3 interacts with proteins known for transporting other proteins within the cell and forming new lysosomes.
That gave them a valuable clue: the CLN3 gene must be a player in these fundamentally important cellular processes of protein transport and lysosome formation. Among the proteins CLN3 interacts with in the Golgi body is a particular receptor called M6PR. The receptor known for its role in recognizing lysosomal enzymes and delivering them to the lysosomes, where they go to work inside these bubble-like structures degrading cellular waste products.
The researchers found that loss of CLN3 led this important M6PR receptor to be broken down within lysosomes. The breakdown, in turn, altered the normal shape of new lysosomes, and that limits their functionality. The researchers also showed that restoring CLN3 in cells that lacked this gene also restored the production of more functional lysosomes and lysosomal enzymes.
Overall, the findings point to a major role for CLN3 in the formation of lysosomes and their ability to function. Importantly, the findings also offer clues for understanding the mechanisms that underlie other forms of lysosomal storage disease, which collectively affect as many as one in every 40,000 people . The work also may have broader implications for common neurodegenerative diseases, such as Parkinson’s and Alzheimer’s disease.
Most of all, this paper demonstrates the power of basic research to define needed molecular targets. It shows how these fundamental studies are helping families affected by Batten disease and supporting their love, hope, and quest for a cure.
 Loss of the batten disease protein CLN3 leads to mis-trafficking of M6PR and defective autophagic-lysosomal reformation. Calcagni’ A, Staiano L, Zampelli N, Minopoli N, Herz NJ, Cullen PJ, Parenti G, De Matteis MA, Grumati P, Ballabio A, et al. Nat Commun. 2023 Jul 3;14(1):3911. doi: 10.1038/s41467-023-39643-7. PMID: 37400440; PMCID: PMC10317969.
 Batten Disease. Boston Children’s Hospital.
 Lysosomal storage diseases. Cleveland Clinic fact sheet, June 27, 2022.
Batten Disease (National Institute of Neurological Disorders and Stroke/NIH)
Rare Diseases (NIH)
Alessia Calcagni (Baylor College of Medicine, Houston, TX)
Andrea Ballabio (Telethon Institute of Genetics and Medicine, Naples, Italy)
NIH Support: National Institute of Neurological Disorders and Stroke; National Cancer Institute; National Center for Advancing Translational Sciences